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

INL Results for Phases I and III of the OECD/NEA MHTGR-350 Benchmark

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

Gerhard Strydom; Javier Ortensi; Sonat Sen

2013-09-01

The Idaho National Laboratory (INL) Very High Temperature Reactor (VHTR) Technology Development Office (TDO) Methods Core Simulation group led the construction of the Organization for Economic Cooperation and Development (OECD) Modular High Temperature Reactor (MHTGR) 350 MW benchmark for comparing and evaluating prismatic VHTR analysis codes. The benchmark is sponsored by the OECD's Nuclear Energy Agency (NEA), and the project will yield a set of reference steady-state, transient, and lattice depletion problems that can be used by the Department of Energy (DOE), the Nuclear Regulatory Commission (NRC), and vendors to assess their code suits. The Methods group is responsible formore » defining the benchmark specifications, leading the data collection and comparison activities, and chairing the annual technical workshops. This report summarizes the latest INL results for Phase I (steady state) and Phase III (lattice depletion) of the benchmark. The INSTANT, Pronghorn and RattleSnake codes were used for the standalone core neutronics modeling of Exercise 1, and the results obtained from these codes are compared in Section 4. Exercise 2 of Phase I requires the standalone steady-state thermal fluids modeling of the MHTGR-350 design, and the results for the systems code RELAP5-3D are discussed in Section 5. The coupled neutronics and thermal fluids steady-state solution for Exercise 3 are reported in Section 6, utilizing the newly developed Parallel and Highly Innovative Simulation for INL Code System (PHISICS)/RELAP5-3D code suit. Finally, the lattice depletion models and results obtained for Phase III are compared in Section 7. The MHTGR-350 benchmark proved to be a challenging simulation set of problems to model accurately, and even with the simplifications introduced in the benchmark specification this activity is an important step in the code-to-code verification of modern prismatic VHTR codes. A final OECD/NEA comparison report will compare the Phase I and III results of all other international participants in 2014, while the remaining Phase II transient case results will be reported in 2015.« less

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

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.

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.

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

PubMed

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

2007-04-01

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

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

PubMed Central

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

2014-01-01

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

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

PubMed

Van Bambeke, Françoise

2014-11-01

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

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.

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

A Phase III Trial Comparing Two Dose-dense, Dose-intensified Approaches (ETC and PM(Cb)) for Neoadjuvant Treatment of Patients With High-risk Early Breast Cancer (GeparOcto)

ClinicalTrials.gov

2017-07-10

Tubular Breast Cancer Stage II; Tubular Breast Cancer Stage III; Mucinous Breast Cancer Stage II; Breast Cancer Female NOS; Invasive Ductal Breast Cancer; HER2 Positive Breast Cancer; Inflammatory Breast Cancer

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.

Ceftaroline Fosamil for the Treatment of Community-Acquired Pneumonia: from FOCUS to CAPTURE.

PubMed

Carreno, Joseph J; Lodise, Thomas P

2014-12-01

Ceftaroline fosamil (ceftaroline hereafter) is the latest addition to the armamentarium for the treatment of patients with community-acquired pneumonia (CAP). It is currently approved by the Food and Drug Administration (FDA) for community-acquired bacterial pneumonia (CABP), which is a recent FDA indication that centers on individuals with documented bacterial pneumonias that arise in the community setting. The purpose of this review is to summarize and discuss the major findings from the Phase III CAP clinical trials as well as the clinical experience with ceftaroline among patients with CAP in the "Ceftaroline Assessment Program and Teflaro(®) Utilization Registry" (CAPTURE). In its two Phase III CAP trials, ceftaroline was compared to ceftriaxone among adults with radiographically confirmed CAP requiring hospitalization who were classified as Pneumonia Outcomes Research Team (PORT) risk class III or IV. Among patients with CAP, clinical success at test of cure was 84.3% vs 77.7% (difference 6.6%, 95% confidence interval [CI]: 1.6-11.8%) in those treated with ceftaroline and ceftriaxone, respectively, across the two Phase III clinical trials. Among patients with a culture-confirmed CABP, day 4 response rates were numerically higher, albeit non-significant, among patients that received ceftaroline vs. ceftriaxone (69.5% for ceftaroline vs. 59.4% for ceftriaxone, difference 10.1%, 95% CI, -0.6% to 20.6%). The efficacy of ceftaroline is supported by real-world observational data from CAPTURE for patients with both CAP and CABP. In addition, the CAPTURE program afforded an opportunity to assess the outcomes of patients who were excluded or limited in the original Phase III trials in a non-comparative fashion. These underrepresented patient populations with CAP included: patients that received prior antibiotics, patients in the ICU, patients with severe renal dysfunction, and those with methicillin-resistant Staphylococcus aureus (MRSA) isolated from respiratory or blood culture. As CAPTURE is a retrospective, non-comparator convenience sample registry, all the findings need to be interpreted with caution.

A "First Principles" Potential Energy Surface for Liquid Water from VRT Spectroscopy of Water Clusters

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

Goldman, N; Leforestier, C; Saykally, R J

We present results of gas phase cluster and liquid water simulations from the recently determined VRT(ASP-W)III water dimer potential energy surface. VRT(ASP-W)III is shown to not only be a model of high ''spectroscopic'' accuracy for the water dimer, but also makes accurate predictions of vibrational ground-state properties for clusters up through the hexamer. Results of ambient liquid water simulations from VRT(ASP-W)III are compared to those from ab initio Molecular Dynamics, other potentials of ''spectroscopic'' accuracy, and to experiment. The results herein represent the first time that a ''spectroscopic'' potential surface is able to correctly model condensed phase properties of water.

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.

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

PubMed

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

2016-04-25

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

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.

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 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

A Phase II/III randomized controlled trial comparing perioperative versus postoperative chemotherapy with mFOLFOX6 for lower rectal cancer with suspected lateral pelvic node metastasis: Japan Clinical Oncology Group Study JCOG1310 (PRECIOUS study).

PubMed

Ohue, Masayuki; Iwasa, Satoru; Kanemitsu, Yukihide; Hamaguchi, Tetsuya; Shiozawa, Manabu; Ito, Masaaki; Yasui, Masayoshi; Katayama, Hiroshi; Mizusawa, Junki; Shimada, Yasuhiro

2017-01-01

A randomized phase II/III trial was started in May 2015 comparing perioperative versus postoperative chemotherapy with modified infusional fluorouracil and folinic acid with oxaliplatin for lower rectal cancer patients with suspected lateral pelvic node metastasis. The standard arm is total mesorectal excision or tumor-specific mesorectal excision with lateral pelvic node dissection (LND) followed by postoperative chemotherapy (modified infusional fluorouracil and folinic acid with oxaliplatin; 12 cycles). The experimental (perioperative chemotherapy) arm is six courses of modified infusional fluorouracil and folinic acid with oxaliplatin before and six courses after total mesorectal excision with lateral pelvic node dissection. The aim of this trial is to confirm the superiority of perioperative chemotherapy. A total of 330 patients will be enrolled over 7 years. The primary endpoint in Phase II part is proportion of R0 resection and that in Phase III part is overall survival. Secondary endpoints are progression-free survival, local progression-free survival, etc. This trial has been registered in the UMIN Clinical Trials Registry as UMIN000017603 [http://www.umin.ac.jp/ctr/index-j.htm]. © The Author 2016. Published by Oxford University Press.

Assessing the comparative effectiveness of newly marketed medications: methodological challenges and implications for drug development.

PubMed

Schneeweiss, S; Gagne, J J; Glynn, R J; Ruhl, M; Rassen, J A

2011-12-01

Comparative-effectiveness research (CER) aims to produce actionable evidence regarding the effectiveness and safety of medical products and interventions as they are used outside of controlled research settings. Although CER evidence regarding medications is particularly needed shortly after market approval, key methodological challenges include (i) potential bias due to channeling of patients to the newly marketed medication because of various patient-, physician-, and system-related factors; (ii) rapid changes in the characteristics of the user population during the early phase of marketing; and (iii) lack of timely data and the often small number of users in the first few months of marketing. We propose a mix of approaches to generate comparative-effectiveness data in the early marketing period, including sequential cohort monitoring with secondary health-care data and propensity score (PS) balancing, as well as extended follow-up of phase III and phase IV trials, indirect comparisons of placebo-controlled trials, and modeling and simulation of virtual trials.

Drop mass transfer in a microfluidic chip compared to a centrifugal contactor

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

Nemer, Martin B.; Roberts, Christine C.; Hughes, Lindsey G.

2014-06-13

A model system was developed for enabling a multiscale understanding of centrifugal-contactor liquid–liquid extraction.The system consisted of Nd(III) + xylenol orange in the aqueous phase buffered to pH =5.5 by KHP, and dodecane + thenoyltrifluroroacetone (HTTA) + tributyphosphate (TBP) in the organic phase. Diffusion constants were measured for neodymium in both the organic and aqueous phases, and the Nd(III) partition coefficients were measured at various HTTA and TBP concentrations. A microfluidic channel was used as a high-shear model environment to observe mass-transfer on a droplet scale with xylenol orange as the aqueous-phase metal indicator; mass-transfer rates were measured quantitatively inmore » both diffusion and reaction limited regimes on the droplet scale. Lastly, the microfluidic results were comparable to observations made for the same system in a laboratory scale liquid–liquid centrifugal contactor, indicating that single drop microfluidic experiments can provide information on mass transfer in complicated flows and geometries.« less

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.

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/

A randomized phase III trial comparing S-1 versus UFT as adjuvant chemotherapy for stage II/III rectal cancer (JFMC35-C1: ACTS-RC).

PubMed

Oki, E; Murata, A; Yoshida, K; Maeda, K; Ikejiri, K; Munemoto, Y; Sasaki, K; Matsuda, C; Kotake, M; Suenaga, T; Matsuda, H; Emi, Y; Kakeji, Y; Baba, H; Hamada, C; Saji, S; Maehara, Y

2016-07-01

Preventing distant recurrence and achieving local control are important challenges in rectal cancer treatment, and use of adjuvant chemotherapy has been studied. However, no phase III study comparing adjuvant chemotherapy regimens for rectal cancer has demonstrated superiority of a specific regimen. We therefore conducted a phase III study to evaluate the superiority of S-1 to tegafur-uracil (UFT), a standard adjuvant chemotherapy regimen for curatively resected stage II/III rectal cancer in Japan, in the adjuvant setting for rectal cancer. The ACTS-RC trial was an open-label, randomized, phase III superiority trial conducted at 222 sites in Japan. Patients aged 20-80 with stage II/III rectal cancer undergoing curative surgery without preoperative therapy were randomly assigned to receive UFT (500-600 mg/day on days 1-5, followed by 2 days rest) or S-1 (80-120 mg/day on days 1-28, followed by 14 days rest) for 1 year. The primary end point was relapse-free survival (RFS), and the secondary end points were overall survival and adverse events. In total, 961 patients were enrolled from April 2006 to March 2009. The primary analysis was conducted in 480 assigned to receive UFT and 479 assigned to receive S-1. Five-year RFS was 61.7% [95% confidence interval (CI) 57.1% to 65.9%] for UFT and 66.4% (95% CI 61.9% to 70.5%) for S-1 [P = 0.0165, hazard ratio (HR): 0.77, 95% CI 0.63-0.96]. Five-year survival was 80.2% (95% CI 76.3% to 83.5%) for UFT and 82.0% (95% CI 78.3% to 85.2%) for S-1. The main grade 3 or higher adverse events were increased alanine aminotransferase and diarrhea (each 2.3%) in the UFT arm and anorexia, diarrhea (each 2.6%), and fatigue (2.1%) in the S-1 arm. One-year S-1 treatment is superior to UFT with respect to RFS and has therefore become a standard adjuvant chemotherapy regimen for stage II/III rectal cancer following curative resection. © The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology.

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

Assessment of Time to Clinical Response, a Proxy for Discharge Readiness, among Hospitalized Patients with Community-Acquired Pneumonia Who Received either Ceftaroline Fosamil or Ceftriaxone in Two Phase III FOCUS Trials

PubMed Central

Anzueto, Antonio R.; Weber, David J.; Shorr, Andrew F.; Yang, Min; Smith, Alexander; Zhao, Qi; Huang, Xingyue; File, Thomas M.

2014-01-01

The primary driver of health care costs for patients with community-acquired pneumonia (CAP) is the hospital length of stay (LOS). Unfortunately, hospital LOS comparisons are difficult to make from phase III CAP trials because of their structured designs and prespecified treatment durations. However, an opportunity still exists to draw inferences about potential LOS differences between treatments through the use of surrogates for hospital discharge. The intent of this study was to quantify the time to a clinical response, a proxy for the time to discharge readiness, among hospitalized CAP patients who received either ceftaroline or ceftriaxone in two phase III CAP FOCUS clinical trials. On the basis of the Infectious Diseases Society of America and American Thoracic Society CAP management guidelines and recent FDA guidance documents for community-acquired bacterial pneumonia, a post hoc adjudication algorithm was constructed a priori to compare the time to a clinical response, a proxy for the time to discharge readiness, between patients who received ceftaroline or ceftriaxone. Overall, 1,116 patients (ceftaroline, n = 562; ceftriaxone, n = 554) from the pooled FOCUS trials met the selection criteria for this analysis. Kaplan-Meier analyses showed that ceftaroline was associated with a shorter time, measured in days, to meeting the clinical response criteria (P = 0.03). Of the patients on ceftaroline, 61.0, 76.1, and 83.6% achieved a clinical response by days 3, 4, and 5, compared to 54.3, 69.8, and 79.3% of the ceftriaxone-treated patients. In the Cox regression, ceftaroline was associated with a shorter time to a clinical response (HR, 1.16, P = 0.02). The methodology employed here provides a framework to draw comparative effectiveness inferences from phase III CAP efficacy trials. (The FOCUS trials whose data were analyzed in this study have been registered at ClinicalTrials.gov under registration no. NCT00621504 and NCT00509106.) PMID:25487791

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

DTIC Science & Technology

1984-10-01

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

Motilin-induced gastric contractions signal hunger in man.

PubMed

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

2016-02-01

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

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.

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.

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.

A 'first principles' potential energy surface for liquid water from VRT spectroscopy of water clusters.

PubMed

Goldman, Nir; Leforestier, Claude; Saykally, R J

2005-02-15

We present results of gas phase cluster and liquid water simulations from the recently determined VRT(ASP-W)III water dimer potential energy surface (the third fitting of the Anisotropic Site Potential with Woermer dispersion to vibration-rotation-tunnelling data). VRT(ASP-W)III is shown to not only be a model of high 'spectroscopic' accuracy for the water dimer, but also makes accurate predictions of vibrational ground-state properties for clusters up through the hexamer. Results of ambient liquid water simulations from VRT(ASP-W)III are compared with those from ab initio molecular dynamics, other potentials of 'spectroscopic' accuracy and with experiment. The results herein represent the first time to the authors' knowledge that a 'spectroscopic' potential surface is able to correctly model condensed phase properties of water.

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

PubMed

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

2004-01-01

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

The case for introducing pre-registered confirmatory pharmacological pre-clinical studies.

PubMed

Kiwanuka, Olivia; Bellander, Bo-Michael; Hånell, Anders

2018-05-01

When evaluating the design of pre-clinical studies in the field of traumatic brain injury, we found substantial differences compared to phase III clinical trials, which in part may explain the difficulties in translating promising experimental drugs into approved treatments. By using network analysis, we also found cases where a large proportion of the studies evaluating a pre-clinical treatment was performed by inter-related researchers, which is potentially problematic. Subjecting all pre-clinical trials to the rigor of a phase III clinical trial is, however, likely not practically achievable. Instead, we repeat the call for a distinction to be made between exploratory and confirmatory pre-clinical studies.

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

Meta-Analysis of Human Factors Engineering Studies Comparing Individual Differences, Practice Effects and Equipment Design Variations.

DTIC Science & Technology

1985-02-21

Approvoid foT public 90Ieleol, 2* . tJni7nited " - . - o . - ’--. * . -... . 1 UNCLASSIFIED S, E CURITY CLASSIFICATION OF THIS PAGE-" REPORT DOCUMENTATION...ACCESSION NO. 11. TITLE (Include Security Classification) . Veta -Analysis of Human Factors Engineering Studies Comparing Individual Differences, Practice...Background C Opportunity D Significance E History III. PHASE I FINAL REPORT A Literature Review B Formal Analysis C Results D Implications for Phase II IV

Cancer trial enrollment after state-mandated reimbursement.

PubMed

Gross, C P; Murthy, V; Li, Y; Kaluzny, A D; Krumholz, H M

2004-07-21

Recruitment of patients into cancer research studies is exceedingly difficult, particularly for early phase trials. Payer reimbursement policies are a frequently cited barrier. We examined whether state policies that ensure coverage of routine medical care costs for cancer trial participants are associated with an increase in clinical trial enrollment. We used logistic Poisson regressions to analyze enrollment in National Cancer Institute phase II and phase III Clinical Trials Cooperative Group trials and compared changes in trial enrollment rates between 1996 and 2001 of privately insured cancer patients who resided in the four states that enacted coverage policies in 1999 with enrollment rates in states without such policies. All statistical tests were two-sided. Trial enrollment rates increased in the coverage and noncoverage states by 24.9% (95% confidence interval [CI] = 22.8% to 27.0%) and 28.8% (95% CI = 27.7% to 29.8%) per year, respectively, from 1996 through 2001. After implementation of the coverage policies in 1999 in four states, there was a 21.7% (95% CI = 3.8% to 42.6%) annual increase in phase II trial enrollment in coverage states, compared with a 15.6% (95% CI = 8.8% to 21.8%) annual decrease in noncoverage states (P<.001). After accounting for secular trend, cancer type, and race in multivariable analyses, the odds ratio (OR) for a phase II trial participant residing in a coverage versus a noncoverage state after 1999 was 1.59 per year (95% CI = 1.22 to 2.07; P =.001). In a multivariable analysis of phase III trial participation, there was a decrease in the odds of residing in a coverage state after 1999 (OR = 0.90, 95% CI = 0.84 to 0.98; P =.011). State coverage policies were associated with a statistically significant increase in phase II cancer trial participation and did not increase phase III cancer trial enrollment.

Abiraterone Improves Survival in Metastatic Prostate Cancer

Cancer.gov

A multinational phase III trial found that the drug abiraterone acetate prolonged the median survival of patients with metastatic castration-resistant prostate cancer by 4 months compared with patients who received a placebo.

Pomalidomide for Multiple Myeloma

Cancer.gov

A summary of results from a phase III trial that compared the combination of pomalidomide (Pomalyst®) and low-dose dexamethasone versus high-dose dexamethasone alone in patients with multiple myeloma that has progressed despite other treatments.

Crizotinib for Advanced Non-Small Cell Lung Cancer

Cancer.gov

A summary of results from an international phase III clinical trial that compared crizotinib versus chemotherapy in previously treated patients with advanced lung cancer whose tumors have an EML4-ALK fusion gene.

Potential additional effect of omentectomy on metabolic syndrome, acute-phase reactants, and inflammatory mediators in grade III obese patients undergoing laparoscopic Roux-en-Y gastric bypass: a randomized trial.

PubMed

Herrera, Miguel F; Pantoja, Juan Pablo; Velázquez-Fernández, David; Cabiedes, Javier; Aguilar-Salinas, Carlos; García-García, Eduardo; Rivas, Alfredo; Villeda, Christian; Hernández-Ramírez, Diego F; Dávila, Andrea; Zaraín, Aarón

2010-07-01

To assess the additional effect of sudden visceral fat reduction by omentectomy on metabolic syndrome, acute-phase reactants, and inflammatory mediators in patients with grade III obesity (G-III O) undergoing laparoscopic Roux-en-Y gastric bypass (LRYGB). Twenty-two patients were randomized into two groups, LRYGB alone or with omentectomy. Levels of interleukin-6, C-reactive protein, tumor necrosis factor-alpha, leptin, adiponectin, glucose, total cholesterol, HDL cholesterol, LDL cholesterol, and triglycerides, as well as clinical characteristics, were evaluated before surgery and at 1, 3, 6, and 12 months after surgery. Results were compared between groups. Baseline characteristics were comparable in both groups. Mean operative time was significantly higher in the group of patients who underwent omentectomy (P < 0.001). Median weight of the omentum was 795 +/- 341 g. In one patient, a duodenal perforation occurred at the time of omentectomy. BMI, blood pressure, glucose, total cholesterol, LDL, and triglycerides significantly improved in both groups at 1, 3, 6, and 12 months of follow-up when compared with basal values. However, there were no consistent statistically significant differences among the groups in terms of metabolic syndrome components, acute-phase reactants, and inflammatory mediators. Omentectomy does not have an ancillary short-term significant impact on the components of metabolic syndrome and does not induce important changes in the inflammatory mediators in patients undergoing LRYGB. Operative time is more prolonged when omentectomy is performed.

Clinical trial spots for cancer patients by tumor type: The cancer trials portfolio at clinicaltrials.gov

PubMed Central

Prasad, Vinay; Goldstein, Jeffery A.

2015-01-01

Background Although participation in cancer clinical trials is low, little is known about the number of available clinical trials, and open spots for patients. Moreover, it is unclear what the relationship is between clinical trial openings and the incidence and mortality of cancer subtypes. Methodology We identified the number of phase I, phase II, and phase III registered at clinicaltrials.gov by cancer (tumor) type. All counts were over the preceding 5 years (2008 to 2013). We compared these counts against the incidence and prevalence of disease reported by Surveillance, Epidemiology, and End Results (SEER) database for 32 common cancers Results From 2008 to 2013, 3879 phase I trials, 4982 phase II trials and 1379 phase III trials concerning a cancer subtype were registered in clinicaltrials.gov. These trials had a cumulative proposed recruitment of 203396, 421502, and 697787 patients, respectively. Trial enrollment varied by tumor type, with both over and under-representation occurring. Conclusion Opportunities to enroll in clinical trials vary by phase and tumor type. Oncologists must remain committed to clinical trials. PMID:26321010

Clinical trial spots for cancer patients by tumour type: The cancer trials portfolio at clinicaltrials.gov.

PubMed

Prasad, Vinay; Goldstein, Jeffery A

2015-11-01

Although participation in cancer clinical trials is low, little is known about the number of available clinical trials, and open spots for patients. Moreover, it is unclear what the relationship is between clinical trial openings and the incidence and mortality of cancer subtypes. We identified the number of phase I, phase II and phase III registered at clinicaltrials.gov by cancer (tumour) type. All counts were over the preceding 5 years (2008-2013). We compared these counts against the incidence and prevalence of disease reported by Surveillance, Epidemiology and End Results (SEER) database for 32 common cancers. From 2008 to 2013, 3879 phase I trials, 4982 phase II trials and 1379 phase III trials concerning a cancer subtype were registered in clinicaltrials.gov. These trials had a cumulative proposed recruitment of 203,396, 421,502 and 697,787 patients, respectively. Trial enrollment varied by tumour type, with both over and under-representation occurring. Opportunities to enroll in clinical trials vary by phase and tumour type. Oncologists must remain committed to clinical trials. Published by Elsevier Ltd.

Antisense inhibition of apoB synthesis with mipomersen reduces plasma apoC-III and apoC-III-containing lipoproteins

PubMed Central

Furtado, Jeremy D.; Wedel, Mark K.; Sacks, Frank M.

2012-01-01

Mipomersen, an antisense oligonucleotide that reduces hepatic production of apoB, has been shown in phase 2 studies to decrease plasma apoB, LDL cholesterol (LDL-C), and triglycerides. ApoC-III inhibits VLDL and LDL clearance, and it stimulates inflammatory responses in vascular cells. Concentrations of VLDL or LDL with apoC-III independently predict cardiovascular disease. We performed an exploratory posthoc analysis on a subset of hypercholesterolemic subjects obtained from a randomized controlled dose-ranging phase 2 study of mipomersen receiving 100, 200, or 300 mg/wk, or placebo for 13 wk (n = 8 each). ApoC-III–containing lipoproteins were isolated by immuno-affinity chromatography and ultracentrifugation. Mipomersen 200 and 300 mg/wk reduced total apoC-III from baseline by 6 mg/dl (38–42%) compared with placebo group (P < 0.01), and it reduced apoC-III in both apoB lipoproteins and HDL. Mipomersen 100, 200, and 300 mg doses reduced apoB concentration of LDL with apoC-III (27%, 38%, and 46%; P < 0.05). Mipomersen reduced apoC-III concentration in HDL. The drug had no effect on apoE concentration in total plasma and in apoB lipoproteins. In summary, antisense inhibition of apoB synthesis reduced plasma concentrations of apoC-III and apoC-III–containing lipoproteins. Lower concentrations of apoC-III and LDL with apoC-III are associated with reduced risk of coronary heart disease (CHD) in epidemiologic studies independent of traditional risk factors. PMID:22301884

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

The structure of the blue luminescent delta-phase of tris(8-hydroxyquinoline)aluminium(III) (Alq3).

PubMed

Cölle, Michael; Dinnebier, Robert E; Brütting, Wolfgang

2002-12-07

The existence of the facial isomer in the delta-phase of Alq3 is proven by X-ray structural analysis, revealing that both the different molecular structure and the weaker overlap of the pi-orbitals of hydroxyquinoline ligands belonging to neighboring Alq3 molecules as compared to other phases (alpha, beta) are likely to be the origin of the significantly different optical properties of delta-Alq3.

New treatments for the motor symptoms of Parkinson's disease.

PubMed

Vijverman, Anne-Catherine; Fox, Susan H

2014-11-01

Levodopa remains the most potent drug to treat motor symptoms in Parkinson's disease (PD); however, motor fluctuations and levodopa-induced dyskinesia that occur with long-term use restrict some of its therapeutic value. Despite these limitations, the medical treatment of PD strives for continuous relief of symptoms using different strategies throughout the course of the illness: increasing the half-life of levodopa, using 'levodopa-sparing agents' and adding non-dopaminergic drugs. New options to 'improve' delivery of levodopa are under investigation, including long-acting levodopa, nasal inhalation and continuous subcutaneous or intrajejunal administration of levodopa. Long-acting dopamine agonists were recently developed and are undergoing further comparative studies to investigate potential superiority over the immediate-release formulations. Non-dopaminergic drugs acting on adenosine receptors, cholinergic, adrenergic, serotoninergic and glutamatergic pathways are newly developed and many are being evaluated in Phase II and Phase III trials. This article focuses on promising novel therapeutic approaches for the management of PD motor symptoms and motor complications. We will provide an update since 2011 on new formulations of current drugs, new drugs with promising results in Phase II and Phase III clinical trials, old drugs with new possibilities and some new potential strategies that are currently in Phase I and II of development (study start date may precede 2011 but are included as study is still ongoing or full data have not yet been published). Negative Phase II and Phase III clinical trials published since 2011 will also be briefly mentioned.

Nab-Paclitaxel Plus Gemcitabine for Metastatic Pancreatic Cancer

Cancer.gov

A summary of results from a phase III trial that compared the combination of albumin-bound paclitaxel (nab-paclitaxel [Abraxane®]) and gemcitabine (Gemzar®) versus gemcitabine alone in patients with metastatic pancreatic cancer.

Radium-223 for Advanced Prostate Cancer

Cancer.gov

A summary of results from a phase III trial that compared radium-223 dichloride plus the best standard of care versus a placebo plus the best standard of care in men with metastatic, castration-resistant prostate cancer.

Enzalutamide Improves Survival in Patients with Metastatic Prostate Cancer

Cancer.gov

A summary of results from an international phase III trial that compared enzalutamide (Xtandi®) and placebo for the treatment of metastatic prostate cancer that had progressed during treatment with androgen deprivation therapy.

Divalent and trivalent gas-phase coordination complexes of californium: evaluating the stability of Cf(II)

DOE PAGES

Dau, Phuong D.; Shuh, David K.; Sturzbecher-Hoehne, Manuel; ...

2016-07-07

The divalent oxidation state is increasingly stable relative to the trivalent state for the later actinide elements, with californium the first actinide to exhibit divalent chemistry under moderate conditions. Although there is evidence for divalent Cf in solution and solid compounds, there are no reports of discrete complexes in which Cf II is coordinated by anionic ligands. Described here is the divalent Cf methanesulfinate coordination complex, Cf II(CH 3SO 2) 3-, prepared in the gas phase by reductive elimination of CH 3SO 2 from Cf III(CH 3SO 2) 4-. Comparison with synthesis of the corresponding Sm and Cm complexes revealsmore » reduction of CfIII and SmIII, and no evidence for reduction of Cm III. This reflects the comparative 3+/2+ reduction potentials: Cf 3+ (-1.60 V) ≈ Sm 3+ (-1.55 V) >> Cm 3+ (-3.7 V). Association of O 2 to the divalent complexes is attributed to formation of superoxides, with recovery of the trivalent oxidation state. Lastly, the new gas-phase chemistry of californium, now the heaviest element to have been studied in this manner, provides evidence for Cf II coordination complexes and similar chemistry of Cf and Sm.« less

Divalent and trivalent gas-phase coordination complexes of californium: evaluating the stability of Cf(II)

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

Dau, Phuong D.; Shuh, David K.; Sturzbecher-Hoehne, Manuel

The divalent oxidation state is increasingly stable relative to the trivalent state for the later actinide elements, with californium the first actinide to exhibit divalent chemistry under moderate conditions. Although there is evidence for divalent Cf in solution and solid compounds, there are no reports of discrete complexes in which Cf II is coordinated by anionic ligands. Described here is the divalent Cf methanesulfinate coordination complex, Cf II(CH 3SO 2) 3-, prepared in the gas phase by reductive elimination of CH 3SO 2 from Cf III(CH 3SO 2) 4-. Comparison with synthesis of the corresponding Sm and Cm complexes revealsmore » reduction of CfIII and SmIII, and no evidence for reduction of Cm III. This reflects the comparative 3+/2+ reduction potentials: Cf 3+ (-1.60 V) ≈ Sm 3+ (-1.55 V) >> Cm 3+ (-3.7 V). Association of O 2 to the divalent complexes is attributed to formation of superoxides, with recovery of the trivalent oxidation state. Lastly, the new gas-phase chemistry of californium, now the heaviest element to have been studied in this manner, provides evidence for Cf II coordination complexes and similar chemistry of Cf and Sm.« less

Speciation of chromium using reversed phase-high performance liquid chromatography coupled to different spectrometric detection methods

NASA Astrophysics Data System (ADS)

Andrle, C. M.; Jakubowski, N.; Broekaert, J. A. C.

1997-02-01

Speciation of Cr(III) and Cr(VI) based on the formation of different complexes with ammonium-pyrrolidinedithioate (APDC) in a continuous flow technique and their preconcentration using solid phase extraction (SPE) have been elaborated and applied to the analysis of waste waters from the galvanic industry. The Cr complexes were separated and determined using reversed phase-high performance liquid chromatography (RP-HPLC) coupled to different detection methods, namely UV-detection, graphite furnace-atomic absorption spectrometry (GF-AAS) and inductively coupled plasma mass spectrometry with hydraulic high pressure nebulization (HHPN/ICP-MS). After optimization the detection limits for Cr(III) and Cr(VI) of all methods are at the μg 1 -1 level and the precision in terms of RSD is 5% ( cCr = 100 μg 1 -1, N = 10). The procedure was applied to the determination of Cr(III) and Cr(VI) at the μg 1 -1 level in galvanic waste waters, and its accuracy was approved by comparing the results with those of independent methods.

Usage, adherence and attrition: how new mothers engage with a nurse-moderated web-based intervention to support maternal and infant health. A 9-month observational study

PubMed Central

Sawyer, Michael G; Reece, Christy E; Bowering, Kerrie; Jeffs, Debra; Sawyer, Alyssa C P; Peters, Jacqueline D; Mpundu-Kaambwa, Christine; Clark, Jennifer J; McDonald, Denise; Mittinty, Murthy N; Lynch, John W

2016-01-01

Objectives To identify factors predicting use, adherence and attrition with a nurse-moderated web-based group intervention designed to support mothers of infants aged 0–6 months. Design 9-Month observational study. Setting Community maternal and child health service. Participants 240 mothers attending initial postnatal health checks at community clinics who were randomly assigned to the intervention arm of a pragmatic preference randomised trial (total randomised controlled trial, n=819; response rate=45%). Intervention In the first week (phase I), mothers were assisted with their first website login by a research assistant. In weeks 2–7 (phase II), mothers participated in the web-based intervention with an expectation of weekly logins. The web-based intervention was comparable to traditional face-to-face new mothers’ groups. During weeks 8–26 (phase III), mothers participated in an extended programme at a frequency of their choosing. Primary outcome measures Number of logins and posted messages. Standard self-report measures assessed maternal demographic and psychosocial characteristics. Results In phase II, the median number of logins was 9 logins (IQR=1–25), and in phase III, it was 10 logins (IQR=0–39). Incident risk ratios from multivariable analyses indicated that compared to mothers with the lowest third of logins in phase I, those with the highest third had 6.43 times as many logins in phase II and 7.14 times in phase III. Fifty per cent of mothers logged-in at least once every 30 days for 147 days after phase I and 44% logged-in at least once in the last 30 days of the intervention. Frequency of logins during phase I was a stronger predictor of mothers’ level of engagement with the intervention than their demographic and psychosocial characteristics. Conclusions Mothers’ early use of web-based interventions could be employed to customise engagement protocols to the circumstances of individual mothers with the aim of improving adherence and reducing attrition with web-based interventions. Trial registration number ACTRN12613000204741; Results. PMID:27496227

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...

Studies on the stripping of cerium from the loaded tbp-kerosene solution

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

Rizk, S.E.; Abdel Rahman, N.; Daoud, J.A.

2008-07-01

The reductive stripping of Ce(IV) from the loaded organic phase (30% TBP in kerosene) was investigated, using two stripping agents, EDTA and H{sub 2}O{sub 2}, in nitric acid. The results are compared to determine the optimum conditions for the reduction of Ce(IV) in the organic phase to Ce(III) in the aqueous phase. For each of the two stripping agents, the effect of different parameters affecting the reduction process was investigated: stripping-agent concentration, nitric acid concentration, phase ratio, shaking time, and temperature. The results are compared and discussed in terms of the conditions required for maximum reductive stripping of Ce(IV). (authors)

Life Cycle Assessment of III-V Precursors for Photovoltaic and Semiconductor Applications

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

Horowitz, Kelsey A; Smith, Brittany L.; Babbitt, Callie W.

This study provides detailed information on the manufacture of III-V metal organic vapor phase epitaxy precursors through extensive literature and patent research. This data informed a cradle-to-gate life cycle assessment of these chemicals. Reported impacts include cumulative energy demand and greenhouse gas emissions. The results were interpreted to identify sources of environmental burden within the life cycle and were compared to energy demand reported in previous studies.

Proposed biosimilar pegfilgrastim (LA-EP2006) compared with reference pegfilgrastim in Asian patients with breast cancer: an exploratory comparison from two Phase III trials.

PubMed

Harbeck, Nadia; Gascon, Pere; Jones, Clyde M; Nixon, Allen; Krendyukov, Andriy; Nakov, Roumen; Li, Yuhan; Blackwell, Kimberly

2017-07-01

This is a pooled subgroup analysis of Asian patients enrolled in two Phase III confirmatory studies comparing proposed biosimilar LA-EP2006 with reference pegfilgrastim in women receiving chemotherapy for breast cancer. Women were randomized to LA-EP2006 (n = 90) or reference (n = 84) pegfilgrastim (Neulasta ® , Amgen, Inc., CA, USA) for ≤6 cycles of TAC chemotherapy. Primary end point was duration of severe neutropenia during Cycle 1 (number of consecutive days with absolute neutrophil count <0.5 × 10 9 /l) with equivalence confirmed if 95% CIs were within a ±1-day margin. Mean duration of severe neutropenia (days) in Cycle 1 was 1.36 ± 0.98 (LA-EP2006) versus 1.35 ± 1.06 (reference) (difference 0.01 days; 95% CI: -0.30-0.32, indicating equivalence). LA-EP2006 showed similar clinical efficacy and safety compared with reference pegfilgrastim.

The co-formulation of insulin degludec and insulin aspart lowers fasting plasma glucose and rates of confirmed and nocturnal hypoglycaemia, independent of baseline glycated haemoglobin levels, disease duration or body mass index: A pooled meta-analysis of phase III studies in patients with type 2 diabetes.

PubMed

Haluzík, Martin; Fulcher, Greg; Pieber, Thomas R; Bardtrum, Lars; Tutkunkardas, Deniz; Rodbard, Helena W

2018-02-16

To investigate whether the proven benefits of insulin degludec (IDeg) combined with insulin aspart (IAsp), known as IDegAsp, given twice daily, extend across a wide spectrum of patients with diabetes. This was a post hoc pooled analysis of 5 phase III randomized, 26-week, open-label, treat-to-target trials comparing IDegAsp twice daily (n = 1111) with one of two comparators: premixed insulin (biphasic insulin aspart 30 [BIAsp 30]) twice daily (n = 561) or IDeg once daily + IAsp (n = 136). Patient data were stratified according to baseline glycated haemoglobin (HbA1c) or fasting plasma glucose (FPG) categories, as well as by baseline duration of diabetes or body mass index (BMI) categories. We conducted a meta-analysis of 5 clinical trials: NCT01513590, NCT01009580, NCT01059812, NCT01680341 and NCT01713530. End-of-trial results were broadly consistent, with differences between IDegAsp and comparators observed in phase III trials. HbA1c results were similar for IDegAsp and the comparators in all baseline characteristic (HbA1c, duration of diabetes or BMI) and category groups (number ranges). Significantly lower FPG level was observed with IDegAsp vs comparators in all baseline characteristic and most category groups (excluding FPG <5.5 mmol/L). Significantly lower insulin doses were observed with IDegAsp vs comparators in all baseline characteristic and half of the category groups, and significantly lower rates of confirmed and nocturnal confirmed hypoglycaemia were observed with IDegAsp vs comparators in all baseline variable and category groups. IDegAsp retains a consistent safety and efficacy profile in patients with different baseline characteristics. © 2018 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.

Improving Participants' Retention in a Smoking Cessation Intervention Using a Community-based Participatory Research Approach.

PubMed

Estreet, Anthony; Apata, Jummai; Kamangar, Farin; Schutzman, Christine; Buccheri, Jane; O'Keefe, Anne-Marie; Wagner, Fernando; Sheikhattari, Payam

2017-01-01

This study compares participant' sretention in three phases of smoking cessation interventions, one provided in a health clinic and the subsequent two in community-based settings. Smoking cessation interventions were conducted in three phases from 2008 to 2015 in two underserved urban communities with low socioeconomic profiles and high rates of smoking ( n = 951). Phase I was conducted in a clinic; Phases II and III were conducted in community venues. In Phases II and III, incremental changes were made based on lessons learned from the previous phases. Retention (attending six or more sessions) was the primary predictor of cessation and was analyzed while controlling for associated factors including age, gender, race, employment, education, and nicotine dependence. Retention increased substantially over the three phases, with rates for attending six or more sessions of 13.8%, 51.9%, and 67.9% in Phases I, II, and III, respectively. Retention was significantly higher in community settings than in the clinic setting (adjusted odds ratio [OR] = 6.7; 95% confidence intervals [CI] = 4.6, 9.8). In addition to the intervention in community venues, predictors of retention included age and unemployment. Higher retention was significantly associated with higher quit rates (adjusted OR = 2.4; 95% CI = 1.5, 3.8). Conducting the intervention in community settings using trained peer motivators rather than health-care providers resulted in significantly higher retention and smoking cessation rates. This was due in part to the ability to tailor cessation classes in the community for specific populations and improving the quality of the intervention based on feedback from participants and community partners.

Effects of bisphenol A and its analogs bisphenol F and S on life parameters, antioxidant system, and response of defensome in the marine rotifer Brachionus koreanus.

PubMed

Park, Jun Chul; Lee, Min-Chul; Yoon, Deok-Seo; Han, Jeonghoon; Kim, Moonkoo; Hwang, Un-Ki; Jung, Jee-Hyun; Lee, Jae-Seong

2018-06-01

To understand the adverse outcome in response to bisphenol A and its analogs bisphenol F and S (BPA, BPF, and BPS), we examined acute toxicity, life parameter, and defensome in the marine rotifer Brachionus koreanus. Among the bisphenol analogs, BPA showed the highest acute toxicity and then BPF and BPS, accordingly in the view of descending magnitude of toxicity. In life parameters including life span and reproduction, BPA, BPF, and BPS were found to cause adverse effect. Both intracellular ROS level and GST activity were significantly increased (P < 0.05) in response to each dosage of bisphenol analogs exposures. In response to bisphenol analogs, defensomes of phase I, II, and III detoxification mechanism demonstrated inverse relationship between the lipophilicity of bisphenol analogs and the expression patterns of defensomes. BPA and BPF were found to have significant modulation (P < 0.05) in the expression of cytochrome P450 (CYP) and GST genes. In phase III, BPS with comparatively lower lipophilicity demonstrated highly diversified expressional pattern, suggesting that BPS is likely caused less toxicity compared to BPA and BPF. In this study, via phase I, II, and III detoxification mechanism, bisphenol A and its analogs F and S demonstrated specific detoxification mechanism in rotifer. Copyright © 2018 Elsevier B.V. All rights reserved.

Sorafenib for Metastatic Thyroid Cancer

Cancer.gov

A summary of results from an international phase III trial that compared sorafenib (Nexavar®) and a placebo for the treatment of locally advanced or metastatic differentiated thyroid cancer that is no longer responding to treatment with radioactive iodine

A post hoc analysis of subgroup outcomes and creatinine in the phase III clinical trial (EMPOWER) of dexpramipexole in ALS.

PubMed

Bozik, Michael E; Mitsumoto, Hiroshi; Brooks, Benjamin R; Rudnicki, Stacy A; Moore, Dan H; Zhang, Bing; Ludolph, Albert; Cudkowicz, Merit E; van den Berg, Leonard H; Mather, James; Petzinger, Thomas; Archibald, Donald

2014-09-01

Our objective was to compare the phase II and phase III (EMPOWER) studies of dexpramipexole in ALS and evaluate potential EMPOWER responder subgroups and biomarkers based on significant inter-study population differences. In a post hoc analysis, we compared the baseline population characteristics of both dexpramipexole studies and analyzed EMPOWER efficacy outcomes and laboratory measures in subgroups defined by significant inter-study differences. Results showed that, compared with phase II, the proportion of El Escorial criteria (EEC) definite participants decreased (p = 0.005), riluzole use increased (p = 0.002), and mean symptom duration increased (p = 0.037) significantly in EMPOWER. Baseline creatinine (p < 0.001) and on-study creatinine change (p < 0.001) correlated significantly with ALSFRS-R in EMPOWER. In the EMPOWER subgroup defined by EEC-definite ALS, riluzole use, and < median symptom duration (15.3 months), dexpramipexole-treated participants had reduced ALSFRS-R slope decline (p = 0.015), decreased mortality (p = 0.011), and reduced creatinine loss (p = 0.003). In conclusion, significant differences existed between the phase II and EMPOWER study populations in ALS clinical trials of dexpramipexole. In a post hoc analysis of EMPOWER subgroups defined by these differences, potential clinical benefits of dexpramipexole were identified in the subgroup of riluzole-treated, short-symptom duration, EEC-definite ALS participants. Creatinine loss correlated with disease progression and was reduced in dexpramipexole-treated participants, suggesting it as a candidate biomarker.

Assessment of time to clinical response, a proxy for discharge readiness, among hospitalized patients with community-acquired pneumonia who received either ceftaroline fosamil or ceftriaxone in two phase III FOCUS trials.

PubMed

Lodise, Thomas P; Anzueto, Antonio R; Weber, David J; Shorr, Andrew F; Yang, Min; Smith, Alexander; Zhao, Qi; Huang, Xingyue; File, Thomas M

2015-02-01

The primary driver of health care costs for patients with community-acquired pneumonia (CAP) is the hospital length of stay (LOS). Unfortunately, hospital LOS comparisons are difficult to make from phase III CAP trials because of their structured designs and prespecified treatment durations. However, an opportunity still exists to draw inferences about potential LOS differences between treatments through the use of surrogates for hospital discharge. The intent of this study was to quantify the time to a clinical response, a proxy for the time to discharge readiness, among hospitalized CAP patients who received either ceftaroline or ceftriaxone in two phase III CAP FOCUS clinical trials. On the basis of the Infectious Diseases Society of America and American Thoracic Society CAP management guidelines and recent FDA guidance documents for community-acquired bacterial pneumonia, a post hoc adjudication algorithm was constructed a priori to compare the time to a clinical response, a proxy for the time to discharge readiness, between patients who received ceftaroline or ceftriaxone. Overall, 1,116 patients (ceftaroline, n=562; ceftriaxone, n=554) from the pooled FOCUS trials met the selection criteria for this analysis. Kaplan-Meier analyses showed that ceftaroline was associated with a shorter time, measured in days, to meeting the clinical response criteria (P=0.03). Of the patients on ceftaroline, 61.0, 76.1, and 83.6% achieved a clinical response by days 3, 4, and 5, compared to 54.3, 69.8, and 79.3% of the ceftriaxone-treated patients. In the Cox regression, ceftaroline was associated with a shorter time to a clinical response (HR, 1.16, P=0.02). The methodology employed here provides a framework to draw comparative effectiveness inferences from phase III CAP efficacy trials. (The FOCUS trials whose data were analyzed in this study have been registered at ClinicalTrials.gov under registration no. NCT00621504 and NCT00509106.). Copyright © 2015, American Society for Microbiology. All Rights Reserved.

ROC curves in clinical chemistry: uses, misuses, and possible solutions.

PubMed

Obuchowski, Nancy A; Lieber, Michael L; Wians, Frank H

2004-07-01

ROC curves have become the standard for describing and comparing the accuracy of diagnostic tests. Not surprisingly, ROC curves are used often by clinical chemists. Our aims were to observe how the accuracy of clinical laboratory diagnostic tests is assessed, compared, and reported in the literature; to identify common problems with the use of ROC curves; and to offer some possible solutions. We reviewed every original work using ROC curves and published in Clinical Chemistry in 2001 or 2002. For each article we recorded phase of the research, prospective or retrospective design, sample size, presence/absence of confidence intervals (CIs), nature of the statistical analysis, and major analysis problems. Of 58 articles, 31% were phase I (exploratory), 50% were phase II (challenge), and 19% were phase III (advanced) studies. The studies increased in sample size from phase I to III and showed a progression in the use of prospective designs. Most phase I studies were powered to assess diagnostic tests with ROC areas >/=0.70. Thirty-eight percent of studies failed to include CIs for diagnostic test accuracy or the CIs were constructed inappropriately. Thirty-three percent of studies provided insufficient analysis for comparing diagnostic tests. Other problems included dichotomization of the gold standard scale and inappropriate analysis of the equivalence of two diagnostic tests. We identify available software and make some suggestions for sample size determination, testing for equivalence in diagnostic accuracy, and alternatives to a dichotomous classification of a continuous-scale gold standard. More methodologic research is needed in areas specific to clinical chemistry.

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.

Methodology of health-related quality of life analysis in phase III advanced non-small-cell lung cancer clinical trials: a critical review.

PubMed

Fiteni, Frédéric; Anota, Amélie; Westeel, Virginie; Bonnetain, Franck

2016-02-18

Health-related quality of life (HRQoL) is recognized as a component endpoint for cancer therapy approvals. The aim of this review was to evaluate the methodology of HRQoL analysis and reporting in phase III clinical trials of first-line chemotherapy in advanced non-small cell lung cancers (NSCLC). A search in MEDLINE databases identified phase III clinical trials in first-line chemotherapy for advanced NSCLC, published between January 2008 to December 2014. Two authors independently extracted information using predefined data abstraction forms. A total of 55 phase III advanced NSCLC trials were identified. HRQoL was declared as an endpoint in 27 studies (49%). Among these 27 studies, The EORTC questionnaire Quality of Life Questionnaire C30 was used in 13 (48%) of the studies and The Functional Assessment of Cancer Therapy-General was used in 12 (44%) trials. The targeted dimensions of HRQoL, the minimal clinically important difference and the statistical approaches for dealing with missing data were clearly specified in 13 (48.1%), 9 (33.3%) and 5 (18.5%) studies, respectively. The most frequent statistical methods for HRQoL analysis were: the mean change from baseline (33.3%), the linear mixed model for repeated measures (22.2%) and time to HRQoL score deterioration (18.5%). For each targeted dimension, the results for each group, the estimated effect size and its precision were clearly reported in 4 studies (14.8%), not clearly reported in 11 studies (40.7%) and not reported at all in 12 studies (44.4%). This review demonstrated the weakness and the heterogeneity of the measurement, analysis, and reporting of HRQoL in phase III advanced NSCLC trials. Precise and uniform recommendations are needed to compare HRQoL results across publications and to provide understandable messages for patients and clinicians.

Ibrutinib Improves Survival in Patients with Previously Treated Chronic Lymphocytic Leukemia

Cancer.gov

A summary of results from an international phase III trial that compared ibrutinib (Imbruvica®) and ofatumumab (Arzerra®) for the treatment of relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).

Obinutuzumab Plus Chlorambucil for Patients with Chronic Lymphocytic Leukemia and Comorbidities

Cancer.gov

A summary of results from an international phase III trial that compared the combination of obinutuzumab (Gazyva™) and chlorambucil (Leukeran®) versus chlorambucil alone, as well as obinutuzumab plus chlorambucil versus rituximab (Rituxan®) plus chloramb

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

RE-VISIT OF HST FUV OBSERVATIONS OF THE HOT-JUPITER SYSTEM HD 209458: NO Si iii DETECTION AND THE NEED FOR COS TRANSIT OBSERVATIONS

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

Ballester, G. E.; Ben-Jaffel, L., E-mail: gilda@lpl.arizona.edu, E-mail: bjaffel@iap.fr

2015-05-10

The discovery of O i atoms and C ii ions in the upper atmosphere of HD 209458b, made with the Hubble Space Telescope Imaging Spectrograph (STIS) using the G140L grating, showed that these heavy species fill an area comparable to the planet’s Roche lobe. The derived ∼10% transit absorption depths require super-thermal processes and/or supersolar abundances. From subsequent Cosmic Origins Spectrograph (COS) observations, C ii absorption was reported with tentative velocity signatures, and absorption by Si iii ions was also claimed in disagreement with a negative STIS G140L detection. Here, we revisit the COS data set showing a severe limitationmore » in the published results from having contrasted the in-transit spectrum against a stellar spectrum averaged from separate observations, at planetary phases 0.27, 0.72, and 0.49. We find variable stellar Si iii and C ii emissions that were significantly depressed not only during transit but also at phase 0.27 compared to phases 0.72 and 0.49. Their respective off-transit 7.5% and 3.1% flux variations are large compared to their reported 8.2 ± 1.4% and 7.8 ± 1.3% transit absorptions. Significant variations also appear in the stellar line shapes, questioning reported velocity signatures. We furthermore present archive STIS G140M transit data consistent with no Si iii absorption, with a negative result of 1.7 ± 18.7 including ∼15% variability. Silicon may still be present at lower ionization states, in parallel with the recent detection of extended magnesium, as Mg i atoms. In this frame, the firm detection of O i and C ii implying solar or supersolar abundances contradicts the recent inference of potential 20–125× subsolar metallicity for HD 209458b.« less

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.

Sequential and simultaneous adsorption of Sb(III) and Sb(V) on ferrihydrite: Implications for oxidation and competition.

PubMed

Qi, Pengfei; Pichler, Thomas

2016-02-01

Antimony (Sb) is a naturally occurring element of growing environmental concern whose toxicity, adsorption behavior and other chemical properties are similar to that of arsenic (As). However, less is known about Sb compared to As. Individual and simultaneous adsorption experiments with Sb(III) and Sb(V) were conducted in batch mode with focus on the Sb speciation of the remaining liquid phase during individual Sb(III) adsorption experiments. The simultaneous adsorption and oxidation of Sb(III) was confirmed by the appearance of Sb(V) in the solution at varying Fe/Sb ratios (500, 100 and 8) and varying pH values (3.8, 7 and 9). This newly formed Sb(V) was subsequently removed from solution at a Fe/Sb ratio of 500 or at a pH of 3.8. However, more or less only Sb(V) was observed in the liquid phase at the end of the experiments at lower Fe/Sb ratios and higher pH, indicating that competition took place between the newly formed Sb(V) and Sb(III), and that Sb(III) outcompeted Sb(V). This was independently confirmed by simultaneous adsorption experiments of Sb(III) and Sb(V) in binary systems. Under such conditions, the presence of Sb(V) had no influence on the adsorption of Sb(III) while Sb(V) adsorption was significantly inhibited by Sb(III) over a wide pH range (4-10). Thus, in the presence of ferrihydrite and under redox conditions, which allow the presence of both Sb species, Sb(V) should be the dominant species in aquatic environments, since Sb(III) is adsorbed preferentially and at the same time oxidized to Sb(V). Copyright © 2015 Elsevier Ltd. All rights reserved.

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...

Meta-analyses and adaptive group sequential designs in the clinical development process.

PubMed

Jennison, Christopher; Turnbull, Bruce W

2005-01-01

The clinical development process can be viewed as a succession of trials, possibly overlapping in calendar time. The design of each trial may be influenced by results from previous studies and other currently proceeding trials, as well as by external information. Results from all of these trials must be considered together in order to assess the efficacy and safety of the proposed new treatment. Meta-analysis techniques provide a formal way of combining the information. We examine how such methods can be used in combining results from: (1) a collection of separate studies, (2) a sequence of studies in an organized development program, and (3) stages within a single study using a (possibly adaptive) group sequential design. We present two examples. The first example concerns the combining of results from a Phase IIb trial using several dose levels or treatment arms with those of the Phase III trial comparing the treatment selected in Phase IIb against a control This enables a "seamless transition" from Phase IIb to Phase III. The second example examines the use of combination tests to analyze data from an adaptive group sequential trial.

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.

Nivolumab for Metastatic Melanoma without a BRAF Mutation

Cancer.gov

A summary of results from an international phase III trial show that nivolumab (Opdivo®) improves overall survival compared with the chemotherapy drug dacarbazine in patients with metastatic melanoma whose tumors do not have a mutation in the BRAF gene.

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.

Improving Participants’ Retention in a Smoking Cessation Intervention Using a Community-based Participatory Research Approach

PubMed Central

Estreet, Anthony; Apata, Jummai; Kamangar, Farin; Schutzman, Christine; Buccheri, Jane; O’Keefe, Anne-Marie; Wagner, Fernando; Sheikhattari, Payam

2017-01-01

Background: This study compares participant’ sretention in three phases of smoking cessation interventions, one provided in a health clinic and the subsequent two in community-based settings. Methods: Smoking cessation interventions were conducted in three phases from 2008 to 2015 in two underserved urban communities with low socioeconomic profiles and high rates of smoking (n = 951). Phase I was conducted in a clinic; Phases II and III were conducted in community venues. In Phases II and III, incremental changes were made based on lessons learned from the previous phases. Retention (attending six or more sessions) was the primary predictor of cessation and was analyzed while controlling for associated factors including age, gender, race, employment, education, and nicotine dependence. Results: Retention increased substantially over the three phases, with rates for attending six or more sessions of 13.8%, 51.9%, and 67.9% in Phases I, II, and III, respectively. Retention was significantly higher in community settings than in the clinic setting (adjusted odds ratio [OR] = 6.7; 95% confidence intervals [CI] = 4.6, 9.8). In addition to the intervention in community venues, predictors of retention included age and unemployment. Higher retention was significantly associated with higher quit rates (adjusted OR = 2.4; 95% CI = 1.5, 3.8). Conclusions: Conducting the intervention in community settings using trained peer motivators rather than health-care providers resulted in significantly higher retention and smoking cessation rates. This was due in part to the ability to tailor cessation classes in the community for specific populations and improving the quality of the intervention based on feedback from participants and community partners. PMID:29416835

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.

Utility of solid phase extraction for spectrophotometric determination of gold in water, jewel and ore samples.

PubMed

Amin, Alaa S

2010-12-01

A highly sensitive, selective and rapid method for the determination μg L(-1) level of Au(III) based on the rapid reaction of Au(III) with 2,3-dichloro-6-(3-carboxy-2-hydroxy-1-naphthylazo)quinoxaline (DCHNAQ) and the solid phase extraction of the colored complex with a reversed phase polymer-based C18 cartridge have been developed. The DCHNAQ reacted with Au(III) to form a violet complex of a molar ratio 3:1 [DCHNAQ to Au(III)] in the presence of 5.0 M of phosphoric acid solution and Triton X-100 medium. This complex was enriched by the solid phase extraction with a polymer-based C18 cartridge. The enrichment factor of 100 was achieved. The molar absorptivity of the complex is 2.73×10(5) l mol(-1) cm(-1) at 633 nm in the measured solution. The system obeys Beer's law in the range of 0.02-1.30 μg ml(-1), whereas the optimum concentration ranges obtained from Ringbom plot was 0.08-1.24 μg ml(-1). The relative standard deviation for ten replicates sample of 0.6 μg ml(-1) level is 1.28%. The detection and quantification limits, are 6.1 and 19.5 ng ml(-1) in the original sample. This method was applied to the determination of gold in water, jewel and ore samples with good results comparing to the GFAAS method. Copyright © 2010 Elsevier B.V. All rights reserved.

Textures of Yukawa coupling matrices in the 2HDM type III

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

Carcamo, A. E.; Martinez, R.; Rodriguez, J.-Alexis

2008-07-02

The quark mass matrices ansatze proposed by Fritzsch, Du-Xing and Fukuyama-Nishiura in the framework of the general two Higgs doublet model are studied. The corresponding Cabbibo-Kobayashi-Maskawa matrix elements are computed in all cases and compared with their experimental values. The complex phases of the anstaze are taken into account and the CP violating phase {delta} is computed. Finally some phenomenology is discussed.

Phenomenological Considerations of the Electric Field Induced Transitions in Improper Ferroelectrics and Ferroelastics. III. Application to Gd2(MoO4)3

NASA Astrophysics Data System (ADS)

Suzuki, Ikuo; Ishibashi, Yoshihiro

1987-02-01

The electric field induced phase transitions are discussed in the improper ferroelectrics and ferroelastics, where the high symmetry phase is assumed to be piezoelectric as in the gadolinium molybdate (GMO). The dependence on the electric field of the polarization is discussed, and the D-E hysteresis loops are compared with the one experimentally observed in GMO.

A randomized controlled Phase III trial comparing 2-weekly docetaxel combined with cisplatin plus fluorouracil (2-weekly DCF) with cisplatin plus fluorouracil (CF) in patients with metastatic or recurrent esophageal cancer: rationale, design and methods of Japan Clinical Oncology Group study JCOG1314 (MIRACLE study).

PubMed

Kataoka, Kozo; Tsushima, Takahiro; Mizusawa, Junki; Hironaka, Shuichi; Tsubosa, Yasuhiro; Kii, Takayuki; Shibuya, Yuichi; Chin, Keisho; Katayama, Hiroshi; Kato, Ken; Fukuda, Haruhiko; Kitagawa, Yuko

2015-05-01

Chemotherapy with cisplatin plus fluorouracil is the current standard treatment for metastatic or recurrent esophageal cancer. We have developed a 2-weekly docetaxel combined with CF regimen and conducted a Phase I/II trial for metastatic or recurrent esophageal cancer (JCOG0807). Promising efficacy and safety were shown in JCOG0807, and we have commenced a Phase III trial in September 2014 to confirm the superiority of 2-weekly DCF to CF for patients with metastatic or recurrent esophageal cancer. A total of 240 patients will be accrued from 41 Japanese institutions over a period of 4 years. The primary end point is overall survival. The secondary end points are progression-free survival, response rate and proportion of adverse events. This trial has been registered in the UMIN Clinical Trials Registry as UMIN000015107 (http://www.umin.ac.jp/ctr/index.htm). © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

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).

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.

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.

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

PubMed

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

2013-08-01

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

Ion Mobility Measurements of Multianionic Metalloporphyrin Dimers: Structural Changes Induced by Countercation Exchange

NASA Astrophysics Data System (ADS)

Schneider, Erik; Brendle, Katrina; Jäger, Patrick; Weis, Patrick; Kappes, Manfred M.

2018-04-01

We present gas-phase structures of dimers of MnIII and FeIII meso-tetra(4-sulfonatophenyl)porphyrin multianions with various amounts of sodium and hydrogen counterions. The structural assignments are achieved by combining mass spectrometry, ion mobility measurements, quantum chemical calculations, and trajectory method collision cross section calculations. For a common charge state, we observe significant topological variations in the dimer structures of [(MTPPS)2+nX](6-n)- (M=MnIII, FeIII; X=H, Na; n = 1-3) induced by replacing hydrogen counterions by sodium. For sodium, the dimer structures are much more compact, a finding that can be rationalized by the stronger interactions of the sodium cations with the anionic sulfonic acid groups of the porphyrins as compared to hydrogen. [Figure not available: see fulltext.

Secukinumab long-term safety experience: A pooled analysis of 10 phase II and III clinical studies in patients with moderate to severe plaque psoriasis.

PubMed

van de Kerkhof, Peter C M; Griffiths, Christopher E M; Reich, Kristian; Leonardi, Craig L; Blauvelt, Andrew; Tsai, Tsen-Fang; Gong, Yankun; Huang, Jiaqing; Papavassilis, Charis; Fox, Todd

2016-07-01

Secukinumab, a fully human anti-interleukin-17A monoclonal antibody, has demonstrated efficacy and safety in patients with moderate to severe plaque psoriasis. We reviewed safety data from the secukinumab psoriasis phase II/III program. Data were pooled from 10 phase II/III secukinumab psoriasis studies. Analysis included 3993 subjects; 3430 received secukinumab, representing 2725 subject-years (SYs) of exposure. Over 52 weeks, for secukinumab 300 mg, 150 mg, and etanercept, respectively, exposure-adjusted incidence rates (IRs) per 100 SYs were comparable across treatments for total adverse events (AEs; 236.1, 239.9, and 243.4, respectively); infections (91.1, 85.3, and 93.7, respectively); serious AEs (7.4, 6.8, and 7.0, respectively); serious infections (1.4, 1.1, and 1.4, respectively); malignant or unspecified tumors (0.77, 0.97, and 0.68, respectively); and adjudicated major adverse cardiovascular events (0.42, 0.35, and 0.34, respectively). AEs were not dose-related except for nonserious, mild/moderate, skin/mucosal candidiasis (IRs 3.55, 1.85, and 1.37 for secukinumab 300 mg, 150 mg, and etanercept, respectively). There was a limited number of patients in comparator groups and the exposure to placebo was short. Secukinumab had a favorable safety profile, had no meaningful difference between the 300- and 150-mg doses and, in terms of safety, was comparable to etanercept over 52 weeks in patients with moderate to severe plaque psoriasis. Copyright © 2016 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.

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

NASA Astrophysics Data System (ADS)

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

2007-06-01

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

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

PubMed

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

2012-08-07

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

Safety and tolerability review of lorcaserin in clinical trials.

PubMed

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

2016-10-01

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

Gender differences in clinical registration trials: is there a real problem?

PubMed Central

Labots, Geert; Jones, Aubrey; de Visser, Saco J.; Burggraaf, Jacobus

2018-01-01

Aims Several studies have reported the under‐representation of women in clinical trials, thereby challenging the external validity of the benefit/risk assessments of launched drugs. Our aim was to determine the extent to which women have been included in clinical trials used for drug registration and to analyse the fraction of women participating in phases I, II and III. Methods We conducted cross‐sectional, structured research into publicly available registration dossiers of Food and Drug Administration (FDA)‐approved drugs that are prescribed frequently. Furthermore, we analysed compounds with high hepatic clearance and a known gender‐related difference in drug response. In a sensitivity analysis, we compared figures with US disease prevalence data. Results For 38 of the initial 137 drugs (28%), sufficient data were reported and publicly available. For these drugs, 185 479 trial participants were included, of whom 47% were female and 44% were male; gender was not reported for 9% of participants. However, the number of female participants varied with the phase of the trial, with 22% females in phase I trials vs. 48% and 49%, respectively, in phase II and III trials. When compared with US disease prevalence data, 10 drugs (26%) had a greater than 20% difference between the proportion of females affected with the disease compared with representation in clinical trials. Conclusions From these publicly available data, there was no evidence of any systematic under‐representation of women in clinical trials. PMID:29293280

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.

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

NASA Astrophysics Data System (ADS)

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

2003-04-01

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

Improved healing of extraperitoneal intestinal anastomoses in the early phase when surrounded by omentum.

PubMed

Pierie, J P; de Graaf, P W; van Dijk, M; Renooij, W; van Vroonhoven, T J; Obertop, H

2000-01-01

The extra-anatomical position of a cervical oesophagogastrostomy is a reason for impaired anastomotic healing, but transposition of the omentum that is covered with mesothelial cells may be a way to improve that. This hypothesis was tested in a rat model. An end-to-end jejuno-jejunostomy was placed subcutaneously in group I (n = 29), subcutaneously surrounded by omentum in group II (n = 29) and intra-abdominally surrounded by omentum in group III (n = 20). After 3, 7 or 14 days, the rats were sacrificed and bursting pressure (BP) of the anastomosis or jejunum was measured and the hydroxyproline (HP) level was determined. In group I 5/29, in group II 2/29 and in group III 0/20 rats died following anastomotic leakage (nonsignificant) and were excluded from other measurements. BP was decreased after 3 days in group I (60+/-9 mm Hg) compared with group II (101+/-8 mm Hg) and group III (107+/-11 mm Hg) (p = 0.002). After 7 days, BP in groups I (122+/-10 mm Hg) and II (132+/-10 mm Hg) were lower as compared with group III (230+/-8 mm Hg) (p<0.001). Differences in HP levels were not statistically significant between the groups after 3, 7 and 14 days. The healing of intestinal anastomoses in an extraperitoneal position is improved in the early phase only when surrounded by omentum. Copyright 2000 S. Karger AG, Basel

The role of multimodal treatment in patients with advanced lung neuroendocrine tumors

PubMed Central

Ungaro, Antonio; Spada, Francesca; Cella, Chiara Alessandra; Pisa, Eleonora; Barberis, Massimo; Grana, Chiara; Zerini, Dario; Bertani, Emilio; Ribero, Dario; Funicelli, Luigi; Bonomo, Guido; Ravizza, Davide; Guarize, Juliana; De Marinis, Filippo; Petrella, Francesco; Del Signore, Ester; Pelosi, Giuseppe; Spaggiari, Lorenzo

2017-01-01

Lung neuroendocrine tumors (NETs) comprise typical (TC) and atypical carcinoids (AC). They represent the well differentiated (WD) or low/intermediate grade forms of lung neuroendocrine neoplasms (NENs). Unlike the lung poorly differentiated NENs, that are usually treated with chemotherapy, lung NETs can be managed with several different therapies, making a multidisciplinary interaction a key point. We critically discussed the multimodal clinical management of patients with advanced lung NETs. Provided that no therapeutic algorithm has been validate so far, each clinical case should be discussed within a NEN-dedicated multidisciplinary team. Among the systemic therapies available for metastatic lung NETs everolimus is the only approved drug, on the basis of the results of the phase III RADIANT-4 trial. Another phase III trial, the SPINET, is ongoing comparing lanreotide with placebo. Peptide receptor radionuclide therapy and chemotherapy were not studied within phase III trials for lung NETs, and they have been reported to be active within retrospective or phase II prospective studies. Temozolomide and oxaliplatin are two interesting chemotherapeutic agents in lung NETs. While some European Institutions were certificated as Centers of Excellence for gastroenteropancreatic NENs by the European Neuroendocrine Tumor Society (ENETS), an equivalent ENETS certification for lung NENs does not exist yet. Ideally a lung NEN-dedicated multidisciplinary tumor board should include NEN-dedicated medical oncologists, thoracic medical oncologist, thoracic surgeons, pathologists, interventional radiologists, endocrinologists, radiotherapists, interventional pneumologists, nuclear physician. PMID:29201453

Phase I/II trial of 2-weekly docetaxel combined with cisplatin plus fluorouracil in metastatic esophageal cancer (JCOG0807)

PubMed Central

Hironaka, Shuichi; Tsubosa, Yasuhiro; Mizusawa, Junki; Kii, Takayuki; Kato, Ken; Tsushima, Takahiro; Chin, Keisho; Tomori, Akihisa; Okuno, Tatsuya; Taniki, Toshikatsu; Ura, Takashi; Matsushita, Hisayuki; Kojima, Takashi; Doki, Yuichiro; Kusaba, Hitoshi; Fujitani, Kazumasa; Taira, Koichi; Seki, Shiko; Nakamura, Tsutomu; Kitagawa, Yuko

2014-01-01

We carried out a phase I/II trial of adding 2-weekly docetaxel to cisplatin plus fluorouracil (CF) therapy (2-weekly DCF regimen) in esophageal cancer patients to investigate its safety and antimetastatic activity. Patients received 2-weekly docetaxel (30 mg/m2 [dose level (DL)1] or 40 mg/m2 [DL2] with a 3 + 3 design in phase I, on days 1 and 15) in combination with fixed-dose CF (80 mg/m2 cisplatin, day 1; 800 mg/m2 fluorouracil, days 1–5) repeated every 4 weeks. The primary endpoint was dose-limiting toxicity (DLT) in phase I and central peer review-based response rate in phase II. At least 22 responders among 50 patients were required to satisfy the primary endpoint with a threshold of 35%. Sixty-two patients were enrolled in phase I and II. In phase I, 10 patients were enrolled with DLT of 0/3 at DL1 and 2/7 in DL2. Considering DLT and treatment compliance, the recommended phase II dose was determined as DL1. In phase II, the response rate was 62% (P < 0.0001; 95% confidence interval, 48–75%); median overall survival and progression-free survival were 11.1 and 5.8 months, respectively. Common grade 3/4 adverse events were neutropenia (25%), anemia (36%), hyponatremia (29%), anorexia (24%), and nausea (11%). No febrile neutropenia was observed. Pneumonitis caused treatment-related death in one patient. The 2-weekly DCF regimen showed promising antimetastatic activity and tolerability. A phase III study comparing this regimen with CF therapy is planned by the Japan Clinical Oncology Group. This study was registered at the UMIN Clinical Trials Registry as UMIN 000001737. PMID:25041052

Accelerating clinical development of HIV vaccine strategies: methodological challenges and considerations in constructing an optimised multi-arm phase I/II trial design.

PubMed

Richert, Laura; Doussau, Adélaïde; Lelièvre, Jean-Daniel; Arnold, Vincent; Rieux, Véronique; Bouakane, Amel; Lévy, Yves; Chêne, Geneviève; Thiébaut, Rodolphe

2014-02-26

Many candidate vaccine strategies against human immunodeficiency virus (HIV) infection are under study, but their clinical development is lengthy and iterative. To accelerate HIV vaccine development optimised trial designs are needed. We propose a randomised multi-arm phase I/II design for early stage development of several vaccine strategies, aiming at rapidly discarding those that are unsafe or non-immunogenic. We explored early stage designs to evaluate both the safety and the immunogenicity of four heterologous prime-boost HIV vaccine strategies in parallel. One of the vaccines used as a prime and boost in the different strategies (vaccine 1) has yet to be tested in humans, thus requiring a phase I safety evaluation. However, its toxicity risk is considered minimal based on data from similar vaccines. We newly adapted a randomised phase II trial by integrating an early safety decision rule, emulating that of a phase I study. We evaluated the operating characteristics of the proposed design in simulation studies with either a fixed-sample frequentist or a continuous Bayesian safety decision rule and projected timelines for the trial. We propose a randomised four-arm phase I/II design with two independent binary endpoints for safety and immunogenicity. Immunogenicity evaluation at trial end is based on a single-stage Fleming design per arm, comparing the observed proportion of responders in an immunogenicity screening assay to an unacceptably low proportion, without direct comparisons between arms. Randomisation limits heterogeneity in volunteer characteristics between arms. To avoid exposure of additional participants to an unsafe vaccine during the vaccine boost phase, an early safety decision rule is imposed on the arm starting with vaccine 1 injections. In simulations of the design with either decision rule, the risks of erroneous conclusions were controlled <15%. Flexibility in trial conduct is greater with the continuous Bayesian rule. A 12-month gain in timelines is expected by this optimised design. Other existing designs such as bivariate or seamless phase I/II designs did not offer a clear-cut alternative. By combining phase I and phase II evaluations in a multi-arm trial, the proposed optimised design allows for accelerating early stage clinical development of HIV vaccine strategies.

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

DOT National Transportation Integrated Search

2009-12-01

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

The CTFA Evaluation of Alternatives Program: an evaluation of in vitro alternatives to the Draize primary eye irritation test. (Phase III) surfactant-based formulations.

PubMed

Gettings, S D; Lordo, R A; Hintze, K L; Bagley, D M; Casterton, P L; Chudkowski, M; Curren, R D; Demetrulias, J L; Dipasquale, L C; Earl, L K; Feder, P I; Galli, C L; Glaza, S M; Gordon, V C; Janus, J; Kurtz, P J; Marenus, K D; Moral, J; Pape, W J; Renskers, K J; Rheins, L A; Roddy, M T; Rozen, M G; Tedeschi, J P; Zyracki, J

1996-01-01

The CTFA Evaluation of Alternatives Program is an evaluation of the relationship between data from the Draize primary eye irritation test and comparable data from a selection of promising in vitro eye irritation tests. In Phase III, data from the Draize test and 41 in vitro endpoints on 25 representative surfactant-based personal care formulations were compared. As in Phase I and Phase II, regression modelling of the relationship between maximum average Draize score (MAS) and in vitro endpoint was the primary approach adopted for evaluating in vitro assay performance. The degree of confidence in prediction of MAS for a given in vitro endpoint is quantified in terms of the relative widths of prediction intervals constructed about the fitted regression curve. Prediction intervals reflect not only the error attributed to the model but also the material-specific components of variation in both the Draize and the in vitro assays. Among the in vitro assays selected for regression modeling in Phase III, the relationship between MAS and in vitro score was relatively well defined. The prediction bounds on MAS were most narrow for materials at the lower or upper end of the effective irritation range (MAS = 0-45), where variability in MAS was smallest. This, the confidence with which the MAS of surfactant-based formulations is predicted is greatest when MAS approaches zero or when MAS approaches 45 (no comment is made on prediction of MAS > 45 since extrapolation beyond the range of observed data is not possible). No single in vitro endpoint was found to exhibit relative superiority with regard to prediction of MAS. Variability associated with Draize test outcome (e.g. in MAS values) must be considered in any future comparisons of in vivo and in vitro test results if the purpose is to predict in vivo response using in vitro data.

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

ERIC Educational Resources Information Center

Mississippi State Dept. of Education, Jackson.

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

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

NASA Astrophysics Data System (ADS)

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

2018-05-01

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

HUBBLE SPACE TELESCOPE EMISSION-LINE GALAXIES AT z ∼ 2: THE MYSTERY OF NEON

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

Zeimann, Gregory R.; Ciardullo, Robin; Gebhardt, Henry

2015-01-01

We use near-infrared grism spectroscopy from the Hubble Space Telescope to examine the strength of [Ne III] λ3869 relative to Hβ, [O II] λ3727, and [O III] λ5007 in 236 low-mass (7.5 ≲ log (M {sub *}/M {sub ☉}) ≲ 10.5) star-forming galaxies in the redshift range 1.90 < z < 2.35. By stacking the data by stellar mass, we show that the [Ne III]/[O II] ratios of the z ∼ 2 universe are marginally higher than those seen in a comparable set of local Sloan Digital Sky Survey galaxies, and that [Ne III]/[O III] is enhanced by ∼0.2 dex.more » We consider the possible explanations for this ∼4σ result, including higher oxygen depletion out of the gas phase, denser H II regions, higher production of {sup 22}Ne via Wolf-Rayet stars, and the existence of a larger population of X-ray obscured active galactic nuclei at z ∼ 2 compared to z ∼ 0. None of these simple scenarios, alone, are favored to explain the observed line ratios. We conclude by suggesting several avenues of future observations to further explore the mystery of enhanced [Ne III] emission.« less

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

PubMed

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

2016-03-23

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

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

PubMed

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

2004-06-17

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

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

ERIC Educational Resources Information Center

Stringfield, Sam; And Others

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

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

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

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

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

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

PubMed

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

2018-05-01

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

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

PubMed Central

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

2017-01-01

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

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

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

PubMed

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

2017-01-01

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

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.

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

PubMed

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

2013-01-01

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

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

PubMed

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

2013-11-18

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

Constitutive modeling of shock response of PTFE

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

Brown, Eric N; Reanyansky, Anatoly D; Bourne, Neil K

2009-01-01

The PTFE (polytetrafluoroethylene) material is complex and attracts attention of the shock physics researchers because it has amorphous and crystalline components. In turn, the crystalline component has four known phases with the high pressure transition to phase III. At the same time, as has been recently studied using spectrometry, the crystalline region is growing with load. Stress and velocity shock-wave profiles acquired recently with embedded gauges demonstrate feature that may be related to impedance mismatches between the regions subjected to some transitions resulting in density and modulus variations. We consider the above mentioned amorphous-to-crystalline transition and the high pressure Phasemore » II-to-III transitions as possible candidates for the analysis. The present work utilizes a multi-phase rate sensitive model to describe shock response of the PTFE material. One-dimensional experimental shock wave profiles are compared with calculated profiles with the kinetics describing the transitions. The objective of this study is to understand the role of the various transitions in the shock response of PTFE.« less

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

PubMed

Crinò, Lucio; Cappuzzo, Federico

2002-06-01

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

Ternary phase equilibria in transition metal-boron-carbon-silicon systems. Part I. Related binary systems, Volume III. Systems Mo-B and W-B. Technical documentary report, 1 November 1964-1 June 1965

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

Rudy, E.; Windisch.

1965-07-01

On the basis of X-ray, melting point, metallographic, and differential thermoanalytical studies on molybdenum-boron and tungsten-boron alloys, constitution diagrams for both binary systems are presented. In the high temperature regions, the newly established phase diagrams differ significantly from previously reported systems. The results are discussed and compared with available literature data.

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

Efficacy of pirfenidone and disease severity of idiopathic pulmonary fibrosis: Extended analysis of phase III trial in Japan.

PubMed

Taguchi, Yoshio; Ebina, Masahito; Hashimoto, Seishu; Ogura, Takashi; Azuma, Arata; Taniguchi, Hiroyuki; Kondoh, Yasuhiro; Suga, Moritaka; Takahashi, Hiroki; Nakata, Koichiro; Sugiyama, Yukihiko; Kudoh, Shoji; Nukiwa, Toshihiro

2015-11-01

A phase III clinical trial of pirfenidone in patients with idiopathic pulmonary fibrosis (IPF) in Japan has revealed that pirfenidone attenuated the decline in vital capacity (VC) and improved progression-free survival (PFS). We conducted an extended analysis of the pirfenidone trial to investigate its efficacy with respect to IPF severity in the trial population. Patients in the phase III trial were stratified by baseline pulmonary functions including %VC predicted, %diffusion capacity for carbon monoxide predicted, and oxygen saturation by pulse oximetry on exertion and were categorized into mild, moderate, and severe groups of functional impairment. The efficacy of pirfenidone for VC and PFS over 52 weeks was compared among the three sub-populations. Of 264 patients, 102 (39%), 90 (34%), and 72 patients (27%) were classified as having mild, moderate, and severe grades of functional impairment, respectively. This classification was associated with arterial oxygen partial pressure at rest and degree of dyspnea at baseline. While pirfenidone attenuated VC decline at all grades of severity, covariance analysis revealed pirfenidone to have better efficacy in the sub-population with mild-grade IPF. Mixed model repeated measures analysis confirmed that pirfenidone markedly attenuated VC decline in patients with mild-grade IPF compared to its effects in patients with moderate or severe IPF. Pirfenidone also improved PFS markedly in patients with mild-grade IPF. This extended analysis suggested that pirfenidone exerted better therapeutic effects in patients with milder IPF. Further analysis with a larger population is needed to confirm these results. Copyright © 2015. Published by Elsevier B.V.

Silodosin: treatment of the signs and symptoms of benign prostatic hyperplasia.

PubMed

Curran, Monique P

2011-05-07

Silodosin is an α-adrenoceptor antagonist with high selectivity for α(1A)- relative to α(1B)- adrenoceptors. In men aged >50 years with benign prostatic hyperplasia (BPH), silodosin 8 mg once daily, compared with placebo, was associated with a significantly more rapid and effective improvement in the total International Prostate Symptom Score (IPSS) and the storage and voiding IPSS subscores in three 12-week, phase III trials conducted in Europe and the US. In the European trial, silodosin was at least as effective as tamsulosin 0.4 mg once daily in improving the total IPSS. Silodosin was significantly more effective than placebo (all three phase III trials) and tamsulosin (European phase III trial) in simultaneously improving nocturia, frequency and incomplete emptying, according to a post hoc analysis. Long-term, open-label extension trials demonstrated that silodosin provided sustained relief of the signs and symptoms of BPH for up to 1 year. Silodosin was generally well tolerated, and was associated with minimal cardiovascular adverse effects. Abnormal ejaculation, a class effect of α(1A)-adrenoceptor antagonists, was the most common silodosin-associated adverse reaction, but resulted in treatment withdrawal of only a limited number of patients. © 2011 Adis Data Information BV. All rights reserved.

Improved synthesis of carbon-clad silica stationary phases.

PubMed

Haidar Ahmad, Imad A; Carr, Peter W

2013-12-17

Previously, we described a novel method for cladding elemental carbon onto the surface of catalytically activated silica by a chemical vapor deposition (CVD) method using hexane as the carbon source and its use as a substitute for carbon-clad zirconia.1,2 In that method, we showed that very close to exactly one uniform monolayer of Al (III) was deposited on the silica by a process analogous to precipitation from homogeneous solution in order to preclude pore blockage. The purpose of the Al(III) monolayer is to activate the surface for subsequent CVD of carbon. In this work, we present an improved procedure for preparing the carbon-clad silica (denoted CCSi) phases along with a new column packing process. The new method yields CCSi phases having better efficiency, peak symmetry, and higher retentivity compared to carbon-clad zirconia. The enhancements were achieved by modifying the original procedure in three ways: First, the kinetics of the deposition of Al(III) were more stringently controlled. Second, the CVD chamber was flushed with a mixture of hydrogen and nitrogen gas during the carbon cladding process to minimize generation of polar sites by oxygen incorporation. Third, the fine particles generated during the CVD process were exhaustively removed by flotation in an appropriate solvent.

Novel therapies for resistant focal segmental glomerulosclerosis (FONT) phase II clinical trial: study design.

PubMed

Trachtman, Howard; Vento, Suzanne; Gipson, Debbie; Wickman, Larysa; Gassman, Jennifer; Joy, Melanie; Savin, Virginia; Somers, Michael; Pinsk, Maury; Greene, Tom

2011-02-10

The lack of adequate randomized clinical trials (RCT) has hindered identification of new therapies that are safe and effective for patients with primary focal segmental glomerulosclerosis (FSGS), especially in patients who fail to respond to corticosteroids and immunosuppressive therapies. Recent basic science advances have led to development of alternative treatments that specifically target aberrant pathways of fibrosis which are relevant to disease progression in FSGS. There is a need for a flexible Phase II study design which will test such novel antifibrotic strategies in order to identify agents suitable for phase III testing. The Novel Therapies for Resistant Focal Segmental Glomerulosclerosis (FONT) project is a multicenter Phase I/II RCT designed to investigate the potential efficacy of novel therapies for resistant FSGS. Adalimumab and galactose will be evaluated against conservative therapy consisting of the combination of lisinopril, losartan and atorvastatin. The sample size is defined to assure that if one of the treatments has a superior response rate compared to that of the other treatments, it will be selected with high probability for further evaluation. Comparison of primary and secondary endpoints in each study arm will enable a choice to be made of which treatments are worthy of further study in future Phase III RCT. This report highlights the key features of the FONT II RCT including the two-step outcome analysis that will expedite achievement of the study objectives. The proposed phase II study design will help to identify promising agents for further testing while excluding ineffective agents. This staged approach can help to prevent large expenditures on unworthy therapeutic agents in the management of serious but rare kidney diseases.

PLCO Ovarian Phase III Validation Study — EDRN Public Portal

Cancer.gov

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

“Direct” Gas-phase Metallicity in Local Analogs of High-redshift Galaxies: Empirical Metallicity Calibrations for High-redshift Star-forming Galaxies

NASA Astrophysics Data System (ADS)

Bian, Fuyan; Kewley, Lisa J.; Dopita, Michael A.

2018-06-01

We study the direct gas-phase oxygen abundance using the well-detected auroral line [O III]λ4363 in the stacked spectra of a sample of local analogs of high-redshift galaxies. These local analogs share the same location as z ∼ 2 star-forming galaxies on the [O III]λ5007/Hβ versus [N II]λ6584/Hα Baldwin–Phillips–Terlevich diagram. This type of analog has the same ionized interstellar medium (ISM) properties as high-redshift galaxies. We establish empirical metallicity calibrations between the direct gas-phase oxygen abundances (7.8< 12+{log}({{O}}/{{H}})< 8.4) and the N2 (log([N II]λ6584/Hα))/O3N2 (log(([O III]λ5007/Hβ)/([N II]λ6584/Hα))) indices in our local analogs. We find significant systematic offsets between the metallicity calibrations for our local analogs of high-redshift galaxies and those derived from the local H II regions and a sample of local reference galaxies selected from the Sloan Digital Sky Survey (SDSS). The N2 and O3N2 metallicities will be underestimated by 0.05–0.1 dex relative to our calibration, if one simply applies the local metallicity calibration in previous studies to high-redshift galaxies. Local metallicity calibrations also cause discrepancies of metallicity measurements in high-redshift galaxies using the N2 and O3N2 indicators. In contrast, our new calibrations produce consistent metallicities between these two indicators. We also derive metallicity calibrations for R23 (log(([O III]λλ4959,5007+[O II]λλ3726,3729)/Hβ)), O32(log([O III]λλ4959,5007/[O II]λλ3726,3729)), {log}([O III]λ5007/Hβ), and log([Ne III]λ3869/[O II]λ3727) indices in our local analogs, which show significant offset compared to those in the SDSS reference galaxies. By comparing with MAPPINGS photoionization models, the different empirical metallicity calibration relations in the local analogs and the SDSS reference galaxies can be shown to be primarily due to the change of ionized ISM conditions. Assuming that temperature structure variations are minimal and ISM conditions do not change dramatically from z ∼ 2 to z ∼ 5, these empirical calibrations can be used to measure relative metallicities in galaxies with redshifts up to z ∼ 5.0 in ground-based observations.

Comparative study on Ce (III) and La (III) solvent extraction and separation from a nitric acid medium by D2EHPA and Cyanex272

NASA Astrophysics Data System (ADS)

Habibpour, R.; Dargahi, M.; Kashi, E.; Bagherpour, M.

2018-01-01

The solvent extraction of Cerium(III) and Lanthanum(III) from nitric acid solution using the organophosphorous extractants Di-(2-ethyl hexyl) phosphate (D2EHPA) and di-2,4,4- trimethylpentyl phosphoric acid (Cyanex272) in kerosene was investigated. In this study, the magnitude of the extraction of Ce(III) was found to be more significant with Cyanex272 than D2EHPA. D2EHPA was found to be a better extractant for La(III). Among the two extractants, Cyanex272 was used for the separation of Ce from La in three stages with an extraction efficiency of 90.2% for Ce. A 556 mg/L Ce solution was used for the scrubbing of La with an efficiency of ≈34%, which required multi stage scrubbing. The study of thermodynamic parameters such as enthalpy, entropy, and Gibbs free energy impart the exothermic and non-spontaneous process. The chemical speciation curves for lanthanum and cerium in the aqueous phase as a function of pH showed that the free La(III) and Ce(III) metal ion species were largely predominate between a pH = 0 and pH = 7.

Fractionation of Fe isotopes during Fe(II) oxidation by a marine photoferrotroph is controlled by the formation of organic Fe-complexes and colloidal Fe fractions

NASA Astrophysics Data System (ADS)

Swanner, Elizabeth D.; Wu, Wenfang; Schoenberg, Ronny; Byrne, James; Michel, F. Marc; Pan, Yongxin; Kappler, Andreas

2015-09-01

Much interest exists in finding mineralogical, organic, morphological, or isotopic biosignatures for Fe(II)-oxidizing bacteria (FeOB) that are retained in Fe-rich sediments, which could indicate the activity of these organisms in Fe-rich seawater, more common in the Precambrian Era. To date, the effort to establish a clear Fe isotopic signature in Fe minerals produced by Fe(II)-oxidizing metabolisms has been thwarted by the large kinetic fractionation incurred as freshly oxidized aqueous Fe(III) rapidly precipitates as Fe(III) (oxyhydr)oxide minerals at near neutral pH. The Fe(III) (oxyhydr)oxide minerals resulting from abiotic Fe(II) oxidation are isotopically heavy compared to the Fe(II) precursor and are not clearly distinguishable from minerals formed by FeOB isotopically. However, in marine hydrothermal systems and Fe(II)-rich springs the minerals formed are often isotopically lighter than expected considering the fraction of Fe(II) that has been oxidized and experimentally-determined fractionation factors. We measured the Fe isotopic composition of aqueous Fe (Feaq) and the final Fe mineral (Feppt) produced in batch experiment using the marine Fe(II)-oxidizing phototroph Rhodovulum iodosum. The δ56Feaq data are best described by a kinetic fractionation model, while the evolution of δ56Feppt appears to be controlled by a separate fractionation process. We propose that soluble Fe(III), and Fe(II) and Fe(III) extracted from the Feppt may act as intermediates between Fe(II) oxidation and Fe(III) precipitation. Based on 57Fe Mössbauer spectroscopy, extended X-ray absorption fine structure (EXAFS) spectroscopy, and X-ray total scattering, we suggests these Fe phases, collectively Fe(II/III)interm, may consist of organic-ligand bound, sorbed, and/or colloidal Fe(II) and Fe(III) mineral phases that are isotopically lighter than the final Fe(III) mineral product. Similar intermediate phases, formed in response to organic carbon produced by FeOB and inorganic ligands (e.g., SiO44- or PO43-), may form in many natural Fe(II)-oxidizing environments. We propose that the formation of these intermediates is likely to occur in organic-rich systems, and thus may have controlled the ultimate isotopic composition of Fe minerals in systems where Fe(II) was being oxidized by or in the presence of microbes in Earth's past.

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.

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

PubMed

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

2018-03-27

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

Apatinib for the treatment of gastric cancer.

PubMed

Geng, Ruixuan; Li, Jin

2015-01-01

Antiangiogenesis therapy plays an important role in cancer treatment. Apatinib mesylate, a small molecule tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor-2, has been recommended as third-line treatment for metastatic gastric cancer patients. The current review summarizes the publications and conference reports relating to apatinib from preclinical and clinical research in gastric cancer. Apatinib showed good safety, tolerance and treatment efficacy in Phase I/II studies. In a Phase III study, apatinib prolonged the median overall survival of patients with chemotherapy-refractory metastatic gastric cancer by 55 days and the median progression-free survival by 25 days compared with placebo. Apatinib is a new treatment option for advanced gastric cancer. Apatinib is expected to have a broader application when it has been evaluated worldwide. The key issues are to find biomarkers and overcome drug resistance.

Is the step-wise tiered approach for ERA of pharmaceuticals useful for the assessment of cancer therapeutic drugs present in marine environment?

PubMed

Aguirre-Martínez, G V; Okello, C; Salamanca, M J; Garrido, C; Del Valls, T A; Martín-Díaz, M L

2016-01-01

Methotrexate (MTX) and tamoxifen (TMX) cancer therapeutic drugs have been detected within the aquatic environment. Nevertheless, MTX and TMX research is essentially bio-medically orientated, with few studies addressing the question of its toxicity in fresh water organisms, and none to its' effect in the marine environment. To the authors' knowledge, Environmental Risk Assessments (ERA) for pharmaceuticals has mainly been designed for freshwater and terrestrial environments (European Medicines Agency-EMEA guideline, 2006). Therefore, the purpose of this research was (1) to assess effect of MTX and TMX in marine organism using the EMEA guideline, (2) to develop an ERA methodology for marine environment, and (3) to evaluate the suitability of including a biomarker approach in Phase III. To reach these aims, a risk assessment of MTX and TMX was performed following EMEA guideline, including a 2-tier approach during Phase III, applying lysosomal membrane stability (LMS) as a screening biomarker in tier-1 and a battery of biochemical biomarkers in tier-2. Results from Phase II indicated that MTX was not toxic for bacteria, microalgae and sea urchin at the concentrations tested, thus no further assessment was required, while TMX indicated a possible risk. Therefore, Phase III was performed for only TMX. Ruditapes philippinarum were exposed during 14 days to TMX (0.1, 1, 10, 50 μg L(-1)). At the end of the experiment, clams exposed to environmental concentration indicated significant changes in LMS compared to the control (p<0.01); thus a second tier was applied. A significant induction of biomarkers (activity of Ethoxyresorufin O-deethylase [EROD], glutathione S-transferase [GST], glutathione peroxidase [GPX], and lipid peroxidation [LPO] levels) was observed in digestive gland tissues of clams compared with control (p<0.01). Finally, this study indicated that MTX was not toxic at an environmental concentration, whilst TMX was potentially toxic for marine biota. This study has shown the necessity to create specific guidelines in order to evaluate effects of pharmaceuticals in marine environment which includes sensitive endpoints. The inadequacy of current EMEA guideline to predict chemotherapy agents toxicity in Phase II was displayed whilst the usefulness of other tests were demonstrated. The 2-tier approach, applied in Phase III, appears to be suitable for an ERA of cancer therapeutic drugs in the marine environment. Copyright © 2015 Elsevier Inc. All rights reserved.

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.

Development of a GMP Phase III purification process for VB4-845, an immunotoxin expressed in E. coli using high cell density fermentation.

PubMed

Premsukh, Arjune; Lavoie, Joelle M; Cizeau, Jeannick; Entwistle, Joycelyn; MacDonald, Glen C

2011-07-01

VB4-845 is a recombinant immunotoxin comprised of an anti-epithelial cell adhesion molecule (EpCAM) scFv fused to a truncated form of the bacterial toxin, Pseudomonas exotoxin A. VB4-845, purified from TB fed-batch fermentation, showed clinical efficacy when administered locally to treat non-muscle invasive bladder cancer (NMIBC) and squamous cell carcinomas of the head and neck (SCCHN). Here, we describe the implementation of an Escherichia coli high cell density (HCD) cultivation and purification process for VB4-845. HCD cultivation was a prerequisite for achieving higher yields necessary for Phase III clinical trials and commercialization. Using this process, the VB4-845 titer in the supernatant was increased by 30-fold over the original TB fed-batch cultivation. To obtain clinical grade material, a process involving a five-step column purification procedure was implemented and led to an overall recovery of ∼ 40%. VB4-845 purity of >97% was achieved after the first three columns following the removal of low-molecular weight product-related impurities and aggregates. Endotoxins were effectively separated from VB4-845 on the Q-columns and by washing the Ni-column with a detergent buffer while host cell proteins were removed using ceramic hydroxyapatite. Comparability studies demonstrated that the purified product from the Phase III process was identical to the Phase II reference standard produced using TB fed-batch fermentation. Copyright © 2011 Elsevier Inc. All rights reserved.

Once-daily USL255 as adjunctive treatment of partial-onset seizures: Randomized phase III study

PubMed Central

Chung, Steve S; Fakhoury, Toufic A; Hogan, R Edward; Nagaraddi, Venkatesh N; Blatt, Ilan; Lawson, Balduin; Arnold, Stephan; Anders, Bob; Clark, Annie M; Laine, Dawn; Meadows, R Shawn; Halvorsen, Mark B

2014-01-01

Objective To evaluate the efficacy and safety of USL255, Qudexy™ XR (topiramate) extended-release capsules, as an adjunctive treatment for refractory partial-onset seizures (POS) in adults taking one to three concomitant antiepileptic drugs. Methods In this global phase III study (PREVAIL; NCT01142193), 249 adults with POS were randomized 1:1 to once-daily USL255 (200 mg/day) or placebo. The primary and key secondary efficacy endpoints were median percent reduction in weekly POS frequency and responder rate (proportion of patients with ≥50% reduction in seizure frequency). Seizure freedom was also assessed. Safety (adverse events, clinical and laboratory findings), as well as treatment effects on quality of life (QOLIE-31-P) and clinical global impression of change (CGI-C), were evaluated. Results Across the entire 11-week treatment phase, USL255 significantly reduced the median percent seizure frequency and significantly improved responder rate compared with placebo. Efficacy over placebo was observed early in treatment, in patients with highly refractory POS, and in those with the most debilitating seizure types (i.e., complex partial, partial secondarily generalized). USL255 was safe and generally well tolerated with a low incidence of neurocognitive adverse events. USL255 was associated with significant clinical improvement without adversely affecting quality of life. Significance The PREVAIL phase III clinical study demonstrated that once-daily USL255 (200 mg/day) significantly improved seizure control and was safe and generally well tolerated with few neurocognitive side effects. PMID:24902983

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.

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.

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.

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...

Conformational space comparison of GnRH and lGnRH-III using molecular dynamics, cluster analysis and Monte Carlo thermodynamic integration.

PubMed

Watts, C R; Mezei, M; Murphy, R F; Lovas, S

2001-04-01

The conformational space available to GnRH and lGnRH-III was compared using 5.2 ns constant temperature and pressure molecular dynamics simulations with explicit TIP3P solvation and the AMBER v. 5.0 force field. Cluster analysis of both trajectories resulted in two groups of conformations. Results of free energy calculations, in agreement with previous experimental data, indicate that a conformation with a turn from residues 5 through 8 is preferred for GnRH in an aqueous environment. By contrast, a conformation with a helix from residues 2 through 7 with a bend from residues 6 through 10 is preferred for lGnRH-III in an aqueous environment. The side chains of His2 and Trp3 in lGnRH-III occupy different regions of phase space and participate in weakly polar interactions different from those in GnRH. The unique conformational properties of lGnRH-III may account for its specific anti cancer activity.

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

ERIC Educational Resources Information Center

Thurber, John C.

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

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

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

C Ma; Q Zhou; F Li

2011-12-31

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

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

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

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

2016-02-01

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

FUSE Observations of the Active Interacting Binary RY Persei

NASA Astrophysics Data System (ADS)

Peters, G. J.; Polidan, R. S.

2003-12-01

RY Per (HD 17034, B4 V + F7 II-III, P=6.86 d) is a massive interacting binary (6.25 M⊙ + 1.60 M⊙, Olson & Plavec 1997, AJ, 113, 425) that displays a variable weak accretion disk that emits in Hα (Barai, et al., preprint). FUSE observations of this system, carried through in 2002 October at phases 0.20, 0.57, and 0.97 and during its total eclipse on 2002 December 8 are presented. The totality data were binned into two phase intervals: 0.0056-0.9976 (after second contact) and 0.0052-0.0089 (just before third contact). Both eclipse observations reveal broad, prominent emission lines of N III (UV1, λ λ 990-992 Å), O VI (UV1, λ λ 1032,1038 Å), N II (UV1, λ λ 1084-1086 Å), Si III (UV5, λ λ 1108,1109,1113 Å), Si IV(UV3, λ λ 1122,1138 Å), and Fe III (UV1, λ λ 1122-32 Å). Emission from C III (UV4, λ 1176 Å) seen during totality in FUSE observations of the Algol binaries V356 Sgr and TT Hya is conspicuously absent. C III (UV1, λ 977 Å) is also absent. This observation combined with the strong presence of N II, III emission suggests that material processed through the CNO cycle in the mass loser is now being transferred to the B star. The FUSE data imply that the emitting plasma is hot ( ˜100,000-300,000 K) and located above/below the orbital plane. The source of this apparent bipolar flow (also seen in V356 Sgr and TT Hya) may be the splash region detected near phase 0.5 in IUE observations of the N V resonance line, but absorption features from this region were not seen in the non-eclipse FUSE observations. A model for the circumstellar material in this system will be presented and the FUSE observations will be compared with those of V356 Sgr and TT Hya. GJP is grateful for support from NASA Grant NAG5-12253.

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.

Switching From Reference Adalimumab to SB5 (Adalimumab Biosimilar) in Patients With Rheumatoid Arthritis: Fifty-Two-Week Phase III Randomized Study Results.

PubMed

Weinblatt, Michael E; Baranauskaite, Asta; Dokoupilova, Eva; Zielinska, Agnieszka; Jaworski, Janusz; Racewicz, Artur; Pileckyte, Margarita; Jedrychowicz-Rosiak, Krystyna; Baek, Inyoung; Ghil, Jeehoon

2018-06-01

The 24-week equivalent efficacy and comparable safety results of the biosimilar SB5 and reference adalimumab (ADA) from the phase III randomized study in patients with moderate-to-severe rheumatoid arthritis (RA) have been reported previously. We undertook this transition study to evaluate patients who switched from ADA to SB5 or who continued to receive SB5 or ADA up to 52 weeks. In this phase III study, patients were initially randomized 1:1 to receive SB5 or ADA (40 mg subcutaneously every other week). At 24 weeks, patients receiving ADA were rerandomized 1:1 to continue with ADA (ADA/ADA group) or to switch to SB5 (ADA/SB5 group) up to week 52; patients receiving SB5 continued with SB5 for 52 weeks (SB5 group). Efficacy, safety, and immunogenicity were evaluated up to 52 weeks. The full analysis set population consisted of 542 patients (269 in the SB5 group, 273 in the ADA overall group [patients who were randomized to receive ADA at week 0], 125 in the ADA/SB5 group, and 129 in the ADA/ADA group). The percentages of patients meeting the American College of Rheumatology 20%, 50%, or 70% improvement criteria (achieving an ACR20, ACR50, or ACR70 response) at week 24 were maintained after the transition from ADA to SB5, and these response rates were comparable across treatment groups throughout the study. ACR20 response rates ranged from 73.4% to 78.8% at week 52. Radiographic progression was minimal and comparable across treatment groups. The safety profile and the incidence of antidrug antibodies were comparable across treatment groups after transition. SB5 was well tolerated over 1 year in patients with RA, with efficacy, safety, and immunogenicity comparable to those of ADA. Switching from ADA to SB5 had no treatment-emergent issues such as increased adverse events, increased immunogenicity, or loss of efficacy. © 2018 The Authors. Arthritis & Rheumatology published by Wiley Periodicals, Inc. on behalf of American College of Rheumatology.

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;…

Development and testing of responder : phase III.

DOT National Transportation Integrated Search

2017-06-28

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

Phase III Early Restoration Meeting | NOAA Gulf Spill Restoration

Science.gov Websites

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

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

Science.gov Websites

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

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

Science.gov Websites

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

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

PubMed

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

2010-10-01

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

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

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

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

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

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

Comparison of the Diagnostic Accuracy of DSC- and Dynamic Contrast-Enhanced MRI in the Preoperative Grading of Astrocytomas.

PubMed

Nguyen, T B; Cron, G O; Perdrizet, K; Bezzina, K; Torres, C H; Chakraborty, S; Woulfe, J; Jansen, G H; Sinclair, J; Thornhill, R E; Foottit, C; Zanette, B; Cameron, I G

2015-11-01

Dynamic contrast-enhanced MR imaging parameters can be biased by poor measurement of the vascular input function. We have compared the diagnostic accuracy of dynamic contrast-enhanced MR imaging by using a phase-derived vascular input function and "bookend" T1 measurements with DSC MR imaging for preoperative grading of astrocytomas. This prospective study included 48 patients with a new pathologic diagnosis of an astrocytoma. Preoperative MR imaging was performed at 3T, which included 2 injections of 5-mL gadobutrol for dynamic contrast-enhanced and DSC MR imaging. During dynamic contrast-enhanced MR imaging, both magnitude and phase images were acquired to estimate plasma volume obtained from phase-derived vascular input function (Vp_Φ) and volume transfer constant obtained from phase-derived vascular input function (K(trans)_Φ) as well as plasma volume obtained from magnitude-derived vascular input function (Vp_SI) and volume transfer constant obtained from magnitude-derived vascular input function (K(trans)_SI). From DSC MR imaging, corrected relative CBV was computed. Four ROIs were placed over the solid part of the tumor, and the highest value among the ROIs was recorded. A Mann-Whitney U test was used to test for difference between grades. Diagnostic accuracy was assessed by using receiver operating characteristic analysis. Vp_ Φ and K(trans)_Φ values were lower for grade II compared with grade III astrocytomas (P < .05). Vp_SI and K(trans)_SI were not significantly different between grade II and grade III astrocytomas (P = .08-0.15). Relative CBV and dynamic contrast-enhanced MR imaging parameters except for K(trans)_SI were lower for grade III compared with grade IV (P ≤ .05). In differentiating low- and high-grade astrocytomas, we found no statistically significant difference in diagnostic accuracy between relative CBV and dynamic contrast-enhanced MR imaging parameters. In the preoperative grading of astrocytomas, the diagnostic accuracy of dynamic contrast-enhanced MR imaging parameters is similar to that of relative CBV. © 2015 by American Journal of Neuroradiology.

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.

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.

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.

Accurate critical pressures for structural phase transitions of group IV, III-V, and II-VI compounds from the SCAN density functional

NASA Astrophysics Data System (ADS)

Shahi, Chandra; Sun, Jianwei; Perdew, John P.

2018-03-01

Most of the group IV, III-V, and II-VI compounds crystallize in semiconductor structures under ambient conditions. Upon application of pressure, they undergo structural phase transitions to more closely packed structures, sometimes metallic phases. We have performed density functional calculations using projector augmented wave (PAW) pseudopotentials to determine the transition pressures for these transitions within the local density approximation (LDA), the Perdew-Burke-Ernzerhof (PBE) generalized gradient approximation (GGA), and the strongly constrained and appropriately normed (SCAN) meta-GGA. LDA underestimates the transition pressure for most of the studied materials. PBE under- or overestimates in many cases. SCAN typically corrects the errors of LDA and PBE for the transition pressure. The accuracy of SCAN is comparable to that of computationally expensive methods like the hybrid functional HSE06, the random phase approximation (RPA), and quantum Monte Carlo (QMC), in cases where calculations with these methods have been reported, but at a more modest computational cost. The improvement from LDA to PBE to SCAN is especially clearcut and dramatic for covalent semiconductor-metal transitions, as for Si and Ge, where it reflects the increasing relative stabilization of the covalent semiconducting phases under increasing functional sophistication.

[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.

Immunogenicity and safety of a novel MMR vaccine (live, freeze-dried) containing the Edmonston-Zagreb measles strain, the Hoshino mumps strain, and the RA 27/3 rubella strain: Results of a randomized, comparative, active controlled phase III clinical trial.

PubMed

Sood, Ashwani; Mitra, Monjori; Joshi, Himanshu Arvind; Nayak, Uma Siddhartha; Siddaiah, Prashanth; Babu, T Ramesh; Mahapatro, Samarendra; Sanmukhani, Jayesh; Gupta, Gaurav; Mittal, Ravindra; Glueck, Reinhard

2017-07-03

This phase III clinical trial was conducted to evaluate the immunogenicity and safety of the single-dose and multi-dose formulations of a novel MMR vaccine (live, freeze-dried) developed by M/s Cadila Healthcare Limited, India (Cadila MMR vaccine), containing the Hoshino mumps strain, compared to that of an existing MMR vaccine (live, freeze-dried) developed by M/s Serum Institute of India Limited, India (Serum MMR vaccine). These two vaccines have similar measles and rubella strains, but different mumps strains (Hoshino in Cadila MMR vaccine, and L-Zagreb in Serum MMR vaccine). Three hundred and twenty-eight subjects of either sex, aged 15-18 months, were randomized in a 2:1 ratio to receive either the Cadila or Serum MMR vaccine. Immunogenicity assessments (IgG antibodies against measles, mumps, and rubella viruses) were done at baseline and 42 d after vaccination. Solicited (local and systemic) and unsolicited adverse events were recorded for up to 42 d following vaccination. The Cadila MMR vaccine was found to be non-inferior to the Serum MMR vaccine in terms of end-of-study proportion of subjects seropositive for anti-measles antibodies (100.0% in both groups), anti-mumps antibodies (94.5% vs. 94.0%), and anti-rubella antibodies (95.5% vs. 91.0%). Both vaccines were well tolerated by all study participants; the most common adverse event reported in both groups was fever, followed by rash. The results of this phase III clinical trial show that the novel Cadila MMR vaccine is non-inferior to the Serum MMR vaccine.

Evaluating Intermittent Androgen-Deprivation Therapy Phase III Clinical Trials: The Devil Is in the Details.

PubMed

Hussain, Maha; Tangen, Catherine; Higano, Celestia; Vogelzang, Nicholas; Thompson, Ian

2016-01-20

Intermittent androgen deprivation (IAD) has been widely tested in prostate cancer. However, phase III trials testing continuous androgen deprivation (CAD) versus IAD have reached inconclusive and seemingly contradictory results. Different design and conduct issues must be critically evaluated to better interpret the results. Seven published phase III trials were examined for prespecified design and outcomes. Treatment specifications; primary end point; superiority versus noninferiority design assumptions, including magnitude of assumed versus observed noninferiority margin (NIM); duration of follow-up; and quality-of-life (QOL) outcomes were considered in terms of the results and conclusions reported. Five trials had a superiority and three had a noninferiority primary hypothesis. Only three trials had a uniform population and overall survival (OS) end point. All trials observed better outcomes in terms of OS and progression-free survival (PFS) than assumed at time of study design, translating into prespecified NIMs or hazard ratios that reflected larger absolute differences in OS or PFS between arms. Lower-than-expected event rates also reduced statistical power for the trials. Other factors, including length of follow-up, cause of death, QOL, and primary end point, and their impact on trial interpretation are discussed. No trial to date has demonstrated survival superiority of IAD compared with CAD. Trials concluding IAD is noninferior to CAD were based on wide NIMs that included clinically important survival differences, not likely to be considered comparable by physicians or patients. Interim analyses relying on short follow-up and including a majority of non-prostate cancer deaths will favor a noninferiority conclusion and should be interpreted cautiously. Adequate follow-up is required to ensure capture of prostate cancer deaths in both superiority and noninferiority trials. © 2015 by American Society of Clinical Oncology.

Efficacy and Safety of Secukinumab in Elderly Subjects with Moderate to Severe Plaque Psoriasis: A Pooled Analysis of Phase III Studies.

PubMed

Körber, Andreas; Papavassilis, Charis; Bhosekar, Vaishali; Reinhardt, Maximilian

2018-02-01

Psoriasis is a chronic inflammatory skin disease, affecting patients of a wide age range, including elderly patients. Elderly patients can respond differently to drug treatments and can be more vulnerable to adverse reactions. There are limited data on biologic therapies for psoriasis in elderly subjects. Secukinumab, a fully human monoclonal antibody that selectively neutralizes IL-17A, has proven significant efficacy in the treatment of moderate to severe psoriasis. A post-hoc analysis of three phase III trials (ERASURE, FIXTURE and CLEAR) was performed to evaluate the efficacy and safety of secukinumab in elderly subjects. Studies were multicentre, randomized, parallel-group, double-blind, 52-week phase III trials in subjects with moderate to severe plaque psoriasis. For efficacy analyses, 67 elderly subjects (≥ 65 years) treated with secukinumab 300 mg were compared with 841 younger subjects (18-64 years). Psoriasis Area and Severity Index (PASI), Dermatological Life Quality Index (DLQI) and safety were analysed. Elderly subjects had higher baseline frequencies of cardiovascular and metabolic disorders. Secukinumab efficacy in elderly subjects was comparable to that in younger subjects throughout 52 weeks of treatment. PASI 75 response was reached by 81.8% of elderly subjects and 79.4% of younger subjects at Week 52. Similar rates of DLQI 0/1 response were observed. The total rate of adverse events was similar between elderly and younger subjects. Secukinumab at the recommended dose (300 mg) is effective and acceptably safe in subjects aged ≥ 65 years with moderate to severe psoriasis, with quality-of-life benefits, despite an increased prevalence of cardiovascular and metabolic comorbidities in this population.

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).

Activity of Eribulin in Patients With Advanced Liposarcoma Demonstrated in a Subgroup Analysis From a Randomized Phase III Study of Eribulin Versus Dacarbazine.

PubMed

Demetri, George D; Schöffski, Patrick; Grignani, Giovanni; Blay, Jean-Yves; Maki, Robert G; Van Tine, Brian A; Alcindor, Thierry; Jones, Robin L; D'Adamo, David R; Guo, Matthew; Chawla, Sant

2017-10-20

Purpose A phase III study comparing eribulin with dacarbazine in patients with advanced liposarcoma (LPS) or leiomyosarcoma showed a significant improvement in overall survival (OS) for the eribulin arm, with a manageable toxicity profile. We now report the histology-specific subgroup analysis of the efficacy and safety of eribulin compared with dacarbazine in patients with LPS, an independently randomized stratified subgroup of this phase III trial. Methods Patients ≥ 18 years with advanced or metastatic dedifferentiated, myxoid/round cell, or pleomorphic LPS incurable by surgery or radiotherapy were included. Patients with Eastern Cooperative Oncology Group performance status ≤ 2 and two or more prior systemic treatment regimens, including one with anthracycline, were randomly assigned 1:1 to receive eribulin mesylate (1.4 mg/m 2 intravenously on days 1 and 8) or dacarbazine (850, 1,000, or 1,200 mg/m 2 intravenously on day 1) every 21 days. OS, progression-free survival (PFS), and safety were analyzed. Results In the LPS subgroup, OS was significantly improved: 15.6 versus 8.4 months (hazard ratio, 0.51; 95% CI, 0.35 to 0.75; P < .001) with eribulin versus dacarbazine, respectively. Longer OS with eribulin was observed in all LPS histologic subtypes and in all geographic regions evaluated. PFS was also improved with eribulin versus dacarbazine (2.9 v 1.7 months, respectively; hazard ratio, 0.52; 95% CI, 0.35 to 0.78; P = .0015). Adverse events were similar between arms. Conclusion In patients with previously treated LPS, eribulin was associated with significantly superior OS and PFS compared with dacarbazine. Eribulin represents an important treatment option for patients with LPS, a sarcoma subtype for which limited effective systemic treatments are available. Further studies are justified to explore the role of eribulin in earlier lines of therapy as well as in combination with other agents.

Pirfenidone Reduces Respiratory-related Hospitalizations in Idiopathic Pulmonary Fibrosis.

PubMed

Ley, Brett; Swigris, Jeffrey; Day, Bann-Mo; Stauffer, John L; Raimundo, Karina; Chou, Willis; Collard, Harold R

2017-09-15

Respiratory-related hospitalizations of patients with idiopathic pulmonary fibrosis (IPF) are more frequent than those for acute IPF exacerbations and are associated with poor outcomes. To compare the risk of nonelective hospitalization by type (all-cause, respiratory related, and non-respiratory related) and death after hospitalization with use of pirfenidone versus placebo over 52 weeks using data derived from three phase III IPF clinical trials. Individual patient data was pooled from three phase III randomized, placebo-controlled studies of pirfenidone for IPF (the two CAPACITY [Clinical Studies Assessing Pirfenidone in IPF: Research of Efficacy and Safety Outcomes] trials and the ASCEND [Assessment of Pirfenidone to Confirm Efficacy and Safety in Idiopathic Pulmonary Fibrosis] trial), including all patients randomized to pirfenidone 2,403 mg/d (n = 623) or placebo (n = 624). The risk of hospitalization over 52 weeks was compared using standard time-to-event methods. Among those hospitalized, the risk of death after hospitalization was compared with adjustment for treatment group propensity. A total of 1,247 patients (692 from the CAPACITY trials and 555 from the ASCEND trial) were included in the pooled analysis. Pirfenidone was associated with lower risk of respiratory-related hospitalization than placebo (7% vs. 12%; hazard ratio [HR], 0.52; 95% confidence interval [CI], 0.36-0.77; P = 0.001), but all-cause (HR, 0.91; 95% CI, 0.70-1.19; P = 0.528) or non-respiratory-related hospitalization (HR, 1.32; 95% CI, 0.92-1.88; P = 0.145) was not. Among those hospitalized for any reason, treatment with pirfenidone was associated with lower risk of death after hospitalization up to 52 weeks after randomization, but this association was no longer significant with longer follow-up. In a pooled analysis of three phase III IPF clinical trials, patients receiving pirfenidone had a lower risk of nonelective respiratory-related hospitalization over the course of 1 year. The effect of pirfenidone on death after hospitalization is uncertain.

Clinical efficacy of raltegravir against B and non-B subtype HIV-1 in phase III clinical studies.

PubMed

Rockstroh, Jürgen K; Teppler, Hedy; Zhao, Jing; Sklar, Peter; Miller, Michael D; Harvey, Charlotte M; Strohmaier, Kim M; Leavitt, Randi Y; Nguyen, Bach-Yen T

2011-07-17

We evaluated the long-term efficacy of raltegravir according to HIV-1 subtype (B and non-B) using data from three phase III studies in treatment-experienced (BENCHMRK-1 and 2) and treatment-naive (STARTMRK) HIV-infected patients. HIV-1 subtypes were identified from baseline plasma specimens using genotypic data of the PhenoSense GT test (Monogram Biosciences, South San Francisco, California, USA). Non-B subtypes were combined for the current analyses due to small numbers of each specific subtype. An observed failure approach was used (only discontinuations due to lack of efficacy were treated as failures). Resistance evaluation was performed in patients with documented virologic failure. Seven hundred and forty-three patients received raltegravir and 519 received comparator (efavirenz in STARTMRK; optimized background therapy in BENCHMRK). Non-B subtype virus (A, A/C, A/D, A/G, A1, AE, AG, B/G, BF, C, D, D/F, F, F1, G, and complex) was isolated at baseline in 98 (13%) raltegravir recipients and 62 (12%) comparator recipients. Subtypes AE and C were most common, isolated in 41 and 43 patients, respectively. The proportion of raltegravir recipients achieving HIV RNA less than 50 copies/ml was similar between non-B and B subtypes (STARTMRK: 94.5 vs. 88.7%; BENCHMRK-1 and 2: 66.7 vs. 60.7%); change in CD4 cell count also was similar between non-B and B subtypes (STARTMRK: 243 vs. 221 cells/μl; BENCHMRK-1 and 2: 121 vs. 144 cells/μl). Phenotypic resistance to raltegravir in non-B virus was associated with integrase mutations observed previously in subtype B virus. In phase III studies in treatment-naive and treatment-experienced patients, raltegravir showed comparable and potent clinical efficacy against B and non-B HIV-1 subtypes.

Phase II Results of RTOG 0537: A Phase II/III Study Comparing Acupuncture-like Transcutaneous Electrical Nerve Stimulation Versus Pilocarpine in Treating Early Radiation-Induced Xerostomia

PubMed Central

Wong, Raimond K. W.; James, Jennifer L.; Sagar, Stephen; Wyatt, Gwen; Nguyen-Tân, Phuc Felix; Singh, Anurag K.; Lukaszczyk, Barbara; Cardinale, Francis; Yeh, Alexander M.; Berk, Lawrence

2011-01-01

Purpose This phase II component of a multi-institutional phase II/III randomized trial assessed the feasibility and preliminary efficacy of acupuncture-like transcutaneous electrical nerve stimulation (ALTENS) in reducing radiation-induced xerostomia. Methods Head and neck cancer patients who were 3–24 months from completing radiotherapy ± chemotherapy (RT±C) and experiencing xerostomia symptoms with basal whole saliva production ≥0.1 ml/min and without recurrence were eligible. Patients received twice weekly ALTENS sessions (24 over 12 weeks) using a Codetron™ unit. The primary objective assessed the feasibility of ALTENS treatment. A patient was considered compliant if 19/24 ALTENS were delivered, with a targeted 85% compliance rate. Secondary objectives measured treatment-related toxicities and ALTENS effect on overall radiation-induced xerostomia burden using the University of Michigan Xerostomia-Related Quality of Life Scale (XeQOLS). Results Of 48 accrued patients, 47 were evaluable. Median age was 60 years; 84% were male, 70% completed RT±C for > 12 months and 21% had received prior pilocarpine. All ALTENS sessions were completed in 34 patients, but 9 and 1 completed 20–23 and 19 sessions respectively, representing a 94% total compliance rate. 6-month XeQOLS scores were available for 35 patients; 30 (86%) achieved a positive treatment response with a mean reduction of 35.9% (SD 36.1). Five patients developed grade 1–2 gastrointestinal toxicity and one had grade 1 pain event. Conclusions ALTENS treatment for radiation-induced xerostomia can be uniformly delivered in a cooperative multicenter setting and has possible beneficial treatment response. Given these results, the phase III component of this study was initiated. PMID:22252927

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…

Joint probability of statistical success of multiple phase III trials.

PubMed

Zhang, Jianliang; Zhang, Jenny J

2013-01-01

In drug development, after completion of phase II proof-of-concept trials, the sponsor needs to make a go/no-go decision to start expensive phase III trials. The probability of statistical success (PoSS) of the phase III trials based on data from earlier studies is an important factor in that decision-making process. Instead of statistical power, the predictive power of a phase III trial, which takes into account the uncertainty in the estimation of treatment effect from earlier studies, has been proposed to evaluate the PoSS of a single trial. However, regulatory authorities generally require statistical significance in two (or more) trials for marketing licensure. We show that the predictive statistics of two future trials are statistically correlated through use of the common observed data from earlier studies. Thus, the joint predictive power should not be evaluated as a simplistic product of the predictive powers of the individual trials. We develop the relevant formulae for the appropriate evaluation of the joint predictive power and provide numerical examples. Our methodology is further extended to the more complex phase III development scenario comprising more than two (K > 2) trials, that is, the evaluation of the PoSS of at least k₀ (k₀≤ K) trials from a program of K total trials. Copyright © 2013 John Wiley & Sons, Ltd.

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

Phase III open-label randomized study of eribulin mesylate versus capecitabine in patients with locally advanced or metastatic breast cancer previously treated with an anthracycline and a taxane.

PubMed

Kaufman, Peter A; Awada, Ahmad; Twelves, Chris; Yelle, Louise; Perez, Edith A; Velikova, Galina; Olivo, Martin S; He, Yi; Dutcus, Corina E; Cortes, Javier

2015-02-20

This phase III randomized trial (ClinicalTrials.gov identifier: NCT00337103) compared eribulin with capecitabine in patients with locally advanced or metastatic breast cancer (MBC). Women with MBC who had received prior anthracycline- and taxane-based therapy were randomly assigned to receive eribulin or capecitabine as their first-, second-, or third-line chemotherapy for advanced/metastatic disease. Stratification factors were human epidermal growth factor receptor-2 (HER2) status and geographic region. Coprimary end points were overall survival (OS) and progression-free survival (PFS). Median OS times for eribulin (n = 554) and capecitabine (n = 548) were 15.9 and 14.5 months, respectively (hazard ratio [HR], 0.88; 95% CI, 0.77 to 1.00; P = .056). Median PFS times for eribulin and capecitabine were 4.1 and 4.2 months, respectively (HR, 1.08; 95% CI, 0.93 to 1.25; P = .30). Objective response rates were 11.0% for eribulin and 11.5% for capecitabine. Global health status and overall quality-of-life scores over time were similar in the treatment arms. Both treatments had manageable safety profiles consistent with their known adverse effects; most adverse events were grade 1 or 2. In this phase III study, eribulin was not shown to be superior to capecitabine with regard to OS or PFS.

A combined Cyanex-923/HEH[EHP]/Dodecane solvent for recovery of transuranic elements from used nuclear fuel

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

Johnson, A.; Nash, K.L.

2013-07-01

The separation of minor actinides from fission product lanthanides remains a primary challenge for enabling the recycle of used nuclear fuel. To minimize the complexity of materials handling, combining extractant processes has become an increasingly attractive option. Unfortunately, combined processes sometimes suffer reduced utility due to strong dipole-dipole interactions between the extractants. The results reported here describe a system based on a combination of commercially available extractants Cyanex-923 and HEH[EHP]. In contrast to other combined extractant systems, these extractant molecules exhibit comparatively weak interactions, reducing the impact of secondary interactions. In this process, mixtures containing equal ratios of Cyanex-923 andmore » HEH[EHP] were seen to co-extract americium and the lanthanides from nitric acid solutions. Stripping of An(III) was effectively achieved through contact with an aqueous phase comprised of glycine (for pH control) and a polyamino-poly-carboxylate stripping reagent that selectively removes An(III) from the extractant phase. The lanthanides can then be stripped from the loaded organic phase contacting with high nitric acid concentrations. Extraction of fission products zirconium and molybdenum was also investigated and potential strategies for their management have been identified. The work presented demonstrates the feasibility of combining Cyanex-923 and HEH[EHP] for separating and recovering the transuranic elements from the Ln(III). (authors)« less

A tutorial on pilot studies: the what, why and how

PubMed Central

2010-01-01

Pilot studies for phase III trials - which are comparative randomized trials designed to provide preliminary evidence on the clinical efficacy of a drug or intervention - are routinely performed in many clinical areas. Also commonly know as "feasibility" or "vanguard" studies, they are designed to assess the safety of treatment or interventions; to assess recruitment potential; to assess the feasibility of international collaboration or coordination for multicentre trials; to increase clinical experience with the study medication or intervention for the phase III trials. They are the best way to assess feasibility of a large, expensive full-scale study, and in fact are an almost essential pre-requisite. Conducting a pilot prior to the main study can enhance the likelihood of success of the main study and potentially help to avoid doomed main studies. The objective of this paper is to provide a detailed examination of the key aspects of pilot studies for phase III trials including: 1) the general reasons for conducting a pilot study; 2) the relationships between pilot studies, proof-of-concept studies, and adaptive designs; 3) the challenges of and misconceptions about pilot studies; 4) the criteria for evaluating the success of a pilot study; 5) frequently asked questions about pilot studies; 7) some ethical aspects related to pilot studies; and 8) some suggestions on how to report the results of pilot investigations using the CONSORT format. PMID:20053272

A Multiphase Validation of Atlas-Based Automatic and Semiautomatic Segmentation Strategies for Prostate MRI

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

Martin, Spencer; Rodrigues, George, E-mail: george.rodrigues@lhsc.on.ca; Department of Epidemiology/Biostatistics, University of Western Ontario, London

2013-01-01

Purpose: To perform a rigorous technological assessment and statistical validation of a software technology for anatomic delineations of the prostate on MRI datasets. Methods and Materials: A 3-phase validation strategy was used. Phase I consisted of anatomic atlas building using 100 prostate cancer MRI data sets to provide training data sets for the segmentation algorithms. In phase II, 2 experts contoured 15 new MRI prostate cancer cases using 3 approaches (manual, N points, and region of interest). In phase III, 5 new physicians with variable MRI prostate contouring experience segmented the same 15 phase II datasets using 3 approaches: manual,more » N points with no editing, and full autosegmentation with user editing allowed. Statistical analyses for time and accuracy (using Dice similarity coefficient) endpoints used traditional descriptive statistics, analysis of variance, analysis of covariance, and pooled Student t test. Results: In phase I, average (SD) total and per slice contouring time for the 2 physicians was 228 (75), 17 (3.5), 209 (65), and 15 seconds (3.9), respectively. In phase II, statistically significant differences in physician contouring time were observed based on physician, type of contouring, and case sequence. The N points strategy resulted in superior segmentation accuracy when initial autosegmented contours were compared with final contours. In phase III, statistically significant differences in contouring time were observed based on physician, type of contouring, and case sequence again. The average relative timesaving for N points and autosegmentation were 49% and 27%, respectively, compared with manual contouring. The N points and autosegmentation strategies resulted in average Dice values of 0.89 and 0.88, respectively. Pre- and postedited autosegmented contours demonstrated a higher average Dice similarity coefficient of 0.94. Conclusion: The software provided robust contours with minimal editing required. Observed time savings were seen for all physicians irrespective of experience level and baseline manual contouring speed.« less

Similar efficacy for phase I trials in comparison with DTIC for advanced malignant melanoma: an analysis of melanoma outcomes in CTEP-sponsored phase I trials 1995-2011.

PubMed

Luke, Jason J; Rubinstein, Lawrence V; Smith, Gary L; Ivy, S Percy; Harris, Pamela J

2013-04-01

After ipilimumab, vemurafenib, and interleukin-2, standard of care chemotherapy for melanoma remains dacarbazine (response rate ∼9%). Despite this, many physicians hesitate to refer patients to phase I protocols given a perceived lack of clinical benefit and potential for harm. To better understand the validity of these perceptions, the experience of all patients with melanoma treated on phase I trials sponsored by the National Cancer Institute-Cancer Therapy Evaluation Program (NCI-CTEP) from 1995 to 2011 were analyzed and compared with the pooled results of six contemporary phase III trials of dacarbazine. A total of 937 patients with melanoma were treated in 148 CTEP phase I trials. The majority were men with a median of two prior therapies (46% receiving prior dacarbazine). Response and clinical benefit rates in these trials were not clinically different from those of dacarbazine (phase I: 6.3 and 26.8% vs. dacarbazine: 8.8 and 27.9%) although grades 3 and 4 toxicity was significantly higher (54 vs. 28%). Efficacy and toxicity were generally consistent within phase I subgroups (targeted agents, immunotherapies, or chemotherapeutics) though targeted therapy was associated with a lower response rate, immunotherapy with lower clinical benefit rate, and chemotherapy with higher incidence of grade 4 toxicity. Thus, the perception of limited efficacy of phase I trials for patients with melanoma was disproven, whereas the perception of toxicity was observed. However, this difference in toxicity may have been largely because of the nature of phase I vs. phase III trials (i.e. more heavily pretreated) and because of the phase I trials often being multiagent as opposed to dacarbazine alone. © 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins.

MO19390 (SAiL): bleeding events in a phase IV study of first-line bevacizumab with chemotherapy in patients with advanced non-squamous NSCLC.

PubMed

Dansin, Eric; Cinieri, Saverio; Garrido, Pilar; Griesinger, Frank; Isla, Dolores; Koehler, Manfred; Kohlhaeufl, Martin

2012-06-01

The clinical benefit and safety profile associated with first-line bevacizumab with doublet chemotherapy in patients with advanced non-squamous non-small cell lung cancer (NSCLC) was established in two large phase III studies, E4599 and AVAiL. SAiL, a single-arm phase IV study, was conducted to evaluate bevacizumab with a range of first-line chemotherapy regimens in a routine oncology practice setting. This analysis of the SAiL data was undertaken to specifically evaluate bleeding adverse events (AEs) in this study, and to explore potential associations between bleeding and baseline patient and disease characteristics. In total, 2212 patients were evaluated. Bleeding AEs (any grade) occurred in 38.2% of patients (grade ≥ 3 bleeding AEs: 3.6%). Grade ≥ 3 pulmonary hemorrhage and central nervous system bleeding events were observed in 0.7% and 0.1% of patients, respectively. The incidence of grade ≥ 3 bleeding AEs was comparable across patient subgroups defined by central tumor location, tumor cavitation, histology, concomitant anticoagulation therapy and age. The majority (88.6%) of bleeding events resolved or improved, 10.2% persisted and 1.3% led to death; 10.2% of bleeding events required bevacizumab interruption or discontinuation. This analysis from the SAiL trial reaffirms a comparable incidence of clinically significant bleeding associated with first-line bevacizumab and chemotherapy as previous phase III studies in NSCLC patients despite less stringent first-line selection criteria. Grade ≥ 3 bleeding appears to be comparable when analyzed for patient and tumor characteristics, including tumor cavitation and concomitant anticoagulation therapy. Most bleeding events resolved or improved, and interruption/discontinuation of bevacizumab was infrequent in a standard oncology practice setting. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

High-accuracy resolver-to-digital conversion via phase locked loop based on PID controller

NASA Astrophysics Data System (ADS)

Li, Yaoling; Wu, Zhong

2018-03-01

The problem of resolver-to-digital conversion (RDC) is transformed into the problem of angle tracking control, and a phase locked loop (PLL) method based on PID controller is proposed in this paper. This controller comprises a typical PI controller plus an incomplete differential which can avoid the amplification of higher-frequency noise components by filtering the phase detection error with a low-pass filter. Compared with conventional ones, the proposed PLL method makes the converter a system of type III and thus the conversion accuracy can be improved. Experimental results demonstrate the effectiveness of the proposed method.

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

A phase III, open label, randomized multicenter controlled trial of oral versus intravenous treosulfan in heavily pretreated recurrent ovarian cancer: a study of the North-Eastern German Society of Gynecological Oncology (NOGGO).

PubMed

Sehouli, Jalid; Tomè, Oliver; Dimitrova, Desislava; Camara, Oumar; Runnebaum, Ingo Bernhard; Tessen, Hans Werner; Rautenberg, Beate; Chekerov, Radoslav; Muallem, Mustafa Zelal; Lux, Michael Patrick; Trarbach, Tanja; Gitsch, Gerald

2017-03-01

In recurrent ovarian cancer (ROC), there is a high demand on effective therapies with a mild toxicity profile. Treosulfan is an alkylating agent approved as oral (p.o.) and intravenous (i.v.) formulation for the treatment of recurrent ovarian cancer. Data on safety and efficacy for either formulation are rare. For the first time we conducted a randomized phase III study comparing both formulations in women with ROC. Patients having received at least two previous lines of chemotherapy were randomly assigned to one of two treatment arms: treosulfan i.v. 7000 mg/m 2 d1 q4w or treosulfan p.o. 600 mg/m 2 d1-28 q8w. Primary endpoint was safety regarding hematological and gastrointestinal toxicity grade III/IV, secondary endpoints were other toxicities, clinical benefit rate (CBR), time to progression (TTP), overall survival (OS) and quality of life. 250 patients were treated with treosulfan i.v. (128) or treosulfan p.o. (122). In general treosulfan therapy was well tolerated in both treatment arms. Leukopenia grade III/IV occurred significantly more frequently in the p.o. arm (3.9% i.v. arm, 14.8% p.o. arm, p = 0.002). Other toxicities were similar in both arms. CBR was comparable between arms (41.4% i.v. arm, 36.9% p.o. arm). No difference in TTP (3.7 months i.v. arm, 3.5 months p.o. arm) or OS (13.6 months i.v. arm, 10.4 months p.o. arm, p = 0.087) occurred. Given the safety and efficacy results treosulfan is an acceptable option for heavily pretreated OC patients. Regarding the toxicity profile the i.v. application was better tolerated with less grade III and IV toxicities.

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

DOE PAGES

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

2016-10-19

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

Voluntary cough production and swallow dysfunction in Parkinson's disease.

PubMed

Pitts, Teresa; Bolser, Donald; Rosenbek, John; Troche, Michelle; Sapienza, Christine

2008-09-01

Cough is important for airway clearance, particularly if penetration/aspiration of foreign material occurs during swallow. Measures of voluntary cough production from ten male participants with stage II-III Parkinson's disease (PD) who showed no videofluorographic evidence of penetration/aspiration (Group 1) were examined and compared with those of ten male participants with stage II-III PD who showed videofluorographic evidence of penetration/aspiration (Group 2). The degree of penetration/aspiration was expertly judged from the videofluorographic examinations of the participants' sequential swallow of a thin, 30-cc bolus. Measured cough parameters included inspiratory phase duration, inspiratory peak flow, compression phase duration, expiratory peak flow, expiratory rise time, and cough volume acceleration. Results indicated significant group differences for the majority of cough measures, except for inspiratory phase duration and inspiratory peak flow. A modest relationship existed between voluntary cough parameters and penetration/aspiration scores. Decreased ability to adequately clear material from the airway with voluntary cough may exacerbate symptoms resulting from penetration/aspiration, particularly for those with neurodegenerative disease. Measurement of voluntary cough may be useful for the evaluation of airway clearance ability.

Voluntary Cough Production and Swallow Dysfunction in Parkinson’s Disease

PubMed Central

Bolser, Donald; Rosenbek, John; Troche, Michelle; Sapienza, Christine

2014-01-01

Cough is important for airway clearance, particularly if penetration/aspiration of foreign material occurs during swallow. Measures of voluntary cough production from ten male participants with stage II–III Parkinson’s disease (PD) who showed no videofluorographic evidence of penetration/aspiration (Group 1) were examined and compared with those of ten male participants with stage II–III PD who showed videofluorographic evidence of penetration/aspiration (Group 2). The degree of penetration/ aspiration was expertly judged from the videofluorographic examinations of the participants’ sequential swallow of a thin, 30-cc bolus. Measured cough parameters included inspiratory phase duration, inspiratory peak flow, compression phase duration, expiratory peak flow, expiratory rise time, and cough volume acceleration. Results indicated significant group differences for the majority of cough measures, except for inspiratory phase duration and inspiratory peak flow. A modest relationship existed between voluntary cough parameters and penetration/aspiration scores. Decreased ability to adequately clear material from the airway with voluntary cough may exacerbate symptoms resulting from penetration/aspiration, particularly for those with neurodegenerative disease. Measurement of voluntary cough may be useful for the evaluation of airway clearance ability. PMID:18483823

Surface Stability and Growth Kinetics of Compound Semiconductors: An Ab Initio-Based Approach

PubMed Central

Kangawa, Yoshihiro; Akiyama, Toru; Ito, Tomonori; Shiraishi, Kenji; Nakayama, Takashi

2013-01-01

We review the surface stability and growth kinetics of III-V and III-nitride semiconductors. The theoretical approach used in these studies is based on ab initio calculations and includes gas-phase free energy. With this method, we can investigate the influence of growth conditions, such as partial pressure and temperature, on the surface stability and growth kinetics. First, we examine the feasibility of this approach by comparing calculated surface phase diagrams of GaAs(001) with experimental results. In addition, the Ga diffusion length on GaAs(001) during molecular beam epitaxy is discussed. Next, this approach is systematically applied to the reconstruction, adsorption and incorporation on various nitride semiconductor surfaces. The calculated results for nitride semiconductor surface reconstructions with polar, nonpolar, and semipolar orientations suggest that adlayer reconstructions generally appear on the polar and the semipolar surfaces. However, the stable ideal surface without adsorption is found on the nonpolar surfaces because the ideal surface satisfies the electron counting rule. Finally, the stability of hydrogen and the incorporation mechanisms of Mg and C during metalorganic vapor phase epitaxy are discussed. PMID:28811438

Emerging pharmacological therapies in schizophrenia: what's new, what's different, what's next?

PubMed

Citrome, Leslie

2016-12-01

There are several new and emerging medication interventions for both the acute and maintenance treatment phases of schizophrenia. Recently approved are 2 new dopamine receptor partial agonists, brexpiprazole and cariprazine, as well as 2 new long-acting injectable antipsychotic formulations, aripiprazole lauroxil and 3-month paliperidone palmitate. Although differences in efficacy compared to other available choices are not expected, the new oral options offer different tolerability profiles that may be attractive for individual patients who have had difficulties with older medications. The new long-acting injectable options provide additional flexibility in terms of increasing the time interval between injections. In Phase III of clinical development is a novel antipsychotic, lumateperone (ITI-007), that appears to have little in the way of significant adverse effects. Deutetrabenazine and valbenazine are agents in Phase III for the treatment of tardive dyskinesia, a condition that can be found among persons receiving chronic antipsychotic therapy. On the horizon are additional injectable formulations of familiar antipsychotics, aripiprazole and risperidone, that may be more convenient than what is presently available.

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.

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.

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

A retrospective analysis of RET translocation, gene copy number gain and expression in NSCLC patients treated with vandetanib in four randomized Phase III studies.

PubMed

Platt, Adam; Morten, John; Ji, Qunsheng; Elvin, Paul; Womack, Chris; Su, Xinying; Donald, Emma; Gray, Neil; Read, Jessica; Bigley, Graham; Blockley, Laura; Cresswell, Carl; Dale, Angela; Davies, Amanda; Zhang, Tianwei; Fan, Shuqiong; Fu, Haihua; Gladwin, Amanda; Harrod, Grace; Stevens, James; Williams, Victoria; Ye, Qingqing; Zheng, Li; de Boer, Richard; Herbst, Roy S; Lee, Jin-Soo; Vasselli, James

2015-03-23

To determine the prevalence of RET rearrangement genes, RET copy number gains and expression in tumor samples from four Phase III non-small-cell lung cancer (NSCLC) trials of vandetanib, a selective inhibitor of VEGFR, RET and EGFR signaling, and to determine any association with outcome to vandetanib treatment. Archival tumor samples from the ZODIAC ( NCT00312377 , vandetanib ± docetaxel), ZEAL ( NCT00418886 , vandetanib ± pemetrexed), ZEPHYR ( NCT00404924 , vandetanib vs placebo) and ZEST ( NCT00364351 , vandetanib vs erlotinib) studies were evaluated by fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) in 944 and 1102 patients. The prevalence of RET rearrangements by FISH was 0.7% (95% CI 0.3-1.5%) among patients with a known result. Seven tumor samples were positive for RET rearrangements (vandetanib, n = 3; comparator, n = 4). 2.8% (n = 26) of samples had RET amplification (innumerable RET clusters, or ≥7 copies in > 10% of tumor cells), 8.1% (n = 76) had low RET gene copy number gain (4-6 copies in ≥40% of tumor cells) and 8.3% (n = 92) were RET expression positive (signal intensity ++ or +++ in >10% of tumor cells). Of RET-rearrangement-positive patients, none had an objective response in the vandetanib arm and one patient responded in the comparator arm. Radiologic evidence of tumor shrinkage was observed in two patients treated with vandetanib and one treated with comparator drug. The objective response rate was similar in the vandetanib and comparator arms for patients positive for RET copy number gains or RET protein expression. We have identified prevalence for three RET biomarkers in a population predominated by non-Asians and smokers. RET rearrangement prevalence was lower than previously reported. We found no evidence of a differential benefit for efficacy by IHC and RET gene copy number gains. The low prevalence of RET rearrangements (0.7%) prevents firm conclusions regarding association of vandetanib treatment with efficacy in the RET rearrangement NSCLC subpopulation. Randomized Phase III clinical trials ( NCT00312377 , ZODIAC; NCT00418886 , ZEAL; NCT00364351 , ZEST; NCT00404924 , ZEPHYR).

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...

COMPARE CPM-RMI Trial: Intramyocardial Transplantation of Autologous Bone Marrow-Derived CD133+ Cells and MNCs during CABG in Patients with Recent MI: A Phase II/III, Multicenter, Placebo-Controlled, Randomized, Double-Blind Clinical Trial.

PubMed

Naseri, Mohammad Hassan; Madani, Hoda; Ahmadi Tafti, Seyed Hossein; Moshkani Farahani, Maryam; Kazemi Saleh, Davood; Hosseinnejad, Hossein; Hosseini, Saeid; Hekmat, Sepideh; Hossein Ahmadi, Zargham; Dehghani, Majid; Saadat, Alireza; Mardpour, Soura; Hosseini, Seyedeh Esmat; Esmaeilzadeh, Maryam; Sadeghian, Hakimeh; Bahoush, Gholamreza; Bassi, Ali; Amin, Ahmad; Fazeli, Roghayeh; Sharafi, Yaser; Arab, Leila; Movahhed, Mansour; Davaran, Saeid; Ramezanzadeh, Narges; Kouhkan, Azam; Hezavehei, Ali; Namiri, Mehrnaz; Kashfi, Fahimeh; Akhlaghi, Ali; Sotoodehnejadnematalahi, Fattah; Vosough Dizaji, Ahmad; Gourabi, Hamid; Syedi, Naeema; Shahverdi, Abdol Hosein; Baharvand, Hossein; Aghdami, Nasser

2018-07-01

The regenerative potential of bone marrow-derived mononuclear cells (MNCs) and CD133+ stem cells in the heart varies in terms of their pro-angiogenic effects. This phase II/III, multicenter and double-blind trial is designed to compare the functional effects of intramyocardial autologous transplantation of both cell types and placebo in patients with recent myocardial infarction (RMI) post-coronary artery bypass graft. This was a phase II/III, randomized, double-blind, placebo-controlled trial COMPARE CPM-RMI (CD133, Placebo, MNCs - recent myocardial infarction) conducted in accordance with the Declaration of Helsinki that assessed the safety and efficacy of CD133 and MNCs compared to placebo in patients with RMI. We randomly assigned 77 eligible RMI patients selected from 5 hospitals to receive CD133+ cells, MNC, or a placebo. Patients underwent gated single photon emission computed tomography assessments at 6 and 18 months post-intramyocardial transplantation. We tested the normally distributed efficacy outcomes with a mixed analysis of variance model that used the entire data set of baseline and between-group comparisons as well as within subject (time) and group×time interaction terms. There were no related serious adverse events reported. The intramyocardial transplantation of both cell types increased left ventricular ejection fraction by 9% [95% confidence intervals (CI): 2.14% to 15.78%, P=0.01] and improved decreased systolic wall thickening by -3.7 (95% CI: -7.07 to -0.42, P=0.03). The CD133 group showed significantly decreased non-viable segments by 75% (P=0.001) compared to the placebo and 60% (P=0.01) compared to the MNC group. We observed this improvement at both the 6- and 18-month time points. Intramyocardial injections of CD133+ cells or MNCs appeared to be safe and efficient with superiority of CD133+ cells for patients with RMI. Although the sample size precluded a definitive statement about clinical outcomes, these results have provided the basis for larger studies to confirm definitive evidence about the efficacy of these cell types (Registration Number: NCT01167751). Copyright© by Royan Institute. All rights reserved.

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

PubMed Central

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

2012-01-01

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

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

PubMed

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

2017-07-01

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

High pressure phase transitions in tetrahedrally coordinated semiconducting compounds

NASA Technical Reports Server (NTRS)

Yu, S. C.; Spain, I. L.; Skelton, E. F.

1978-01-01

New experimental results are reported for structural transitions at high pressure in several III-V compounds and two II-VI compounds. These data, together with earlier results, are then compared with the predictions of model calculations of Van Vechten. Experimental transition pressures are often at variance with calculated values. However, his calculation assumes that the high pressure phase is metallic, with the beta-Sn structure. The present results show that several compounds assume an ionic NaCl structure at high pressure, while others have neither the beta-Sn nor NaCl structure.

Tunnel Junction Development Using Hydride Vapor Phase Epitaxy

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

Ptak, Aaron J.; Simon, John D.; Schulte, Kevin L.

We demonstrate for the first time III-V tunnel junctions grown using hydride vapor phase epitaxy (HVPE) with peak tunneling currents >8 A/cm 2, sufficient for operation of a multijunction device to several hundred suns of concentration. Multijunction solar cells rely on tunneling interconnects between subcells to enable series connection with minimal voltage loss, but tunnel junctions have never been shown using the HVPE growth method. HVPE has recently reemerged as a low-cost growth method for high-quality III-V materials and devices, including the growth of high-efficiency III-V solar cells. We previously showed single-junction GaAs solar cells with conversion efficiencies of ~24%more » with a path forward to equal or exceed the practical efficiency limits of crystalline Si. Moving to a multijunction device structure will allow for even higher efficiencies with minimal impact on cost, necessitating the development of tunnel interconnects. Here in this paper, we demonstrate the performance of both isolated HVPE-grown tunnel junctions, as well as single-junction GaAs solar cell structures with a tunnel junction incorporated into the contact region. We observe no degradation in device performance compared to a structure without the added junction.« less

Tunnel Junction Development Using Hydride Vapor Phase Epitaxy

DOE PAGES

Ptak, Aaron J.; Simon, John D.; Schulte, Kevin L.; ...

2017-10-18

We demonstrate for the first time III-V tunnel junctions grown using hydride vapor phase epitaxy (HVPE) with peak tunneling currents >8 A/cm 2, sufficient for operation of a multijunction device to several hundred suns of concentration. Multijunction solar cells rely on tunneling interconnects between subcells to enable series connection with minimal voltage loss, but tunnel junctions have never been shown using the HVPE growth method. HVPE has recently reemerged as a low-cost growth method for high-quality III-V materials and devices, including the growth of high-efficiency III-V solar cells. We previously showed single-junction GaAs solar cells with conversion efficiencies of ~24%more » with a path forward to equal or exceed the practical efficiency limits of crystalline Si. Moving to a multijunction device structure will allow for even higher efficiencies with minimal impact on cost, necessitating the development of tunnel interconnects. Here in this paper, we demonstrate the performance of both isolated HVPE-grown tunnel junctions, as well as single-junction GaAs solar cell structures with a tunnel junction incorporated into the contact region. We observe no degradation in device performance compared to a structure without the added junction.« less

Anthropometrics and Body Composition in Adults with High-Grade Gliomas: Effects of Disease-Related Variables.

PubMed

Bertoli, Simona; Battezzati, Alberto; Petruzzi, Alessandra; Leone, Alessandro; De Amicis, Ramona; Tramacere, Elena; Meda, Maddalena; Foppiani, Andrea; Silvani, Antonio; Lamperti, Elena

2018-04-01

Nutritional status in adults with high-grade gliomas (HGGs) has been poorly investigated. We studied anthropometrics and fat mass (FM), fat free mass (FFM), and body water in HGGs patients also in relation to disease-related variables. Fifty-one patients (17 III and 34 IV-grade) and fifty-one control group (CG) matched for sex, age, and BMI were enrolled. Neurological scales, anthropometry, bioimpedance, and blood sampling were performed and analyzed according to grade, lesion location, extent of resection, phase of treatment, current steroids and antiepileptic therapy, and age of patient. 41.2% were overweight and 15.7% obese. Compared to the CG, HGGs had similar anthropometrics and body composition. IV-grade, compared to the III, had higher BMI, waist circumference, FM and lower FFM. Only patients during concomitant radio and chemotherapy showed a negative BMI variation from baseline. In conclusion, overnutrition occurs in almost 6 out of 10 HGGs patients and is more relevant in IV-grade. Throughout all the treatment phases, there is a higher risk of weight loss occurred only during concomitant radio and chemotherapy. Body composition showed no specific features compared to controls. These results may assist intervention studies directed towards neurometabolic dietary treatment. Nutritional screening is warranted during the time course of disease.

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.

Survival results of a randomised two-by-two factorial phase II trial comparing neoadjuvant chemotherapy with two and four courses of S-1 plus cisplatin (SC) and paclitaxel plus cisplatin (PC) followed by D2 gastrectomy for resectable advanced gastric cancer.

PubMed

Yoshikawa, Takaki; Morita, Satoshi; Tanabe, Kazuaki; Nishikawa, Kazuhiro; Ito, Yuichi; Matsui, Takanori; Fujitani, Kazumasa; Kimura, Yutaka; Fujita, Junya; Aoyama, Toru; Hayashi, Tsutomu; Cho, Haruhiko; Tsuburaya, Akira; Miyashita, Yumi; Sakamoto, Junichi

2016-07-01

The prognosis for stage III gastric cancer is unsatisfactory by D2 gastrectomy and S-1 adjuvant chemotherapy. Both S-1 plus cisplatin (SC) and paclitaxel plus cisplatin (PC) are promising regimens as neoadjuvant chemotherapy; however, the optimal duration remains unclear. In this 2×2 randomised phase II trial, stage III gastric cancer patients, those with a prognosis corresponding to stage III, and macroscopically resectable stage IV cases were randomised to two or four courses of S-1 (80 mg/m(2) for 21 d with 1 week rest)/cisplatin (60 mg/m(2) at day 8) or PC (80 and 25 mg/m(2), respectively, on days 1, 8, and 15 with 1 week rest) as neoadjuvant chemotherapy. The primary end-point was the 3-year overall survival (OS). Between October 2009 and July 2011, 83 patients received 2 courses of SC (n=21), 4 courses of SC (n=20), 2 courses of PC (n=21) and 4 courses of PC (n=21). The 3-year OS was 60.9% for SC and 64.3% for PC and 64.3% for the two courses and 61.0% for the four courses. Subset analyses demonstrated no subgroup which showed any potential survival benefit by PC in comparison to SC or by four courses as in comparison to two courses. Two courses of SC as neoadjuvant chemotherapy are recommended as a test arm of a future phase III study for patients with locally advanced gastric cancer. UMIN-000002595. Copyright © 2016 The Author(s). Published by Elsevier Ltd.. All rights reserved.

Structure of the CFA/III major pilin subunit CofA from human enterotoxigenic Escherichia coli determined at 0.90 Å resolution by sulfur-SAD phasing.

PubMed

Fukakusa, Shunsuke; Kawahara, Kazuki; Nakamura, Shota; Iwashita, Takaki; Baba, Seiki; Nishimura, Mitsuhiro; Kobayashi, Yuji; Honda, Takeshi; Iida, Tetsuya; Taniguchi, Tooru; Ohkubo, Tadayasu

2012-10-01

CofA, a major pilin subunit of colonization factor antigen III (CFA/III), forms pili that mediate small-intestinal colonization by enterotoxigenic Escherichia coli (ETEC). In this study, the crystal structure of an N-terminally truncated version of CofA was determined by single-wavelength anomalous diffraction (SAD) phasing using five sulfurs in the protein. Given the counterbalance between anomalous signal strength and the undesired X-ray absorption of the solvent, diffraction data were collected at 1.5 Å resolution using synchrotron radiation. These data were sufficient to elucidate the sulfur substructure at 1.38 Å resolution. The low solvent content (29%) of the crystal necessitated that density modification be performed with an additional 0.9 Å resolution data set to reduce the phase error caused by the small sulfur anomalous signal. The CofA structure showed the αβ-fold typical of type IVb pilins and showed high structural homology to that of TcpA for toxin-coregulated pili of Vibrio cholerae, including spatial distribution of key residues critical for pilin self-assembly. A pilus-filament model of CofA was built by computational docking and molecular-dynamics simulation using the previously reported filament model of TcpA as a structural template. This model revealed that the CofA filament surface was highly negatively charged and that a 23-residue-long loop between the α1 and α2 helices filled the gap between the pilin subunits. These characteristics could provide a unique binding epitope for the CFA/III pili of ETEC compared with other type IVb pili.

Pulsatile luteinizing hormone patterns in the follicular phase of the menstrual cycle, polycystic ovarian disease (PCOD) and non-PCOD secondary amenorrhea.

PubMed

Burger, C W; Korsen, T; van Kessel, H; van Dop, P A; Caron, F J; Schoemaker, J

1985-12-01

To characterize the oscillations of plasma LH in normally cycling and amenorrheic women, three groups of women were studied: I, normal women during the follicular phase of the cycle (n = 9); II, women with polycystic ovarian disease (PCOD; n = 11); and III, women with non-PCOD secondary amenorrhea (n = 12). Blood samples were obtained at 10-min intervals for 6 h on 2 separate days. A pulse was defined as an increase in LH at least 20% over the preceding lowest value (nadir). Since LHRH release immediately follows the nadir of the LH levels, the nadir interval (NI) was used for analysis. For analysis, the results from 1 day were selected at random from each subject, and from each day, the same number of NIs also were randomly selected. When two NIs from each patient were selected, the median NI was 75 min in group I, 45 min in group II, and 45 min in group III. When three or four NIs were chosen, the median NI was 60 min in group I, 50 min in group II, and 40 min in group III. The differences between the groups were statistically significant. When three NIs were selected, the mean of the corresponding LH amplitudes was 2.8 U/liter in group I, 6.0 U/liter in group II, and 1.5 U/liter in group III. The differences between these groups were statistically significant. Thus, the NI in PCOD patients was shorter than that during the follicular phase of the cycle, but this short NI is not unique for PCOD, since the NI in non-PCOD secondary amenorrhea patients was even smaller. The LH amplitude was higher in PCOD and lower in non-PCOD secondary amenorrhea compared to that during the follicular phase of the cycle. The decrease in NI in PCOD and/or non-PCOD secondary amenorrhea vs. the NI of the follicular phase could be explained by either a higher frequency of LHRH pulses from the hypothalamus or an increased sensitivity of the pituitary leading to a greater response of the pituitary to LHRH pulses.

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.

Palbociclib: A Novel Cyclin-Dependent Kinase Inhibitor for Hormone Receptor-Positive Advanced Breast Cancer.

PubMed

Mangini, Neha S; Wesolowski, Robert; Ramaswamy, Bhuvaneswari; Lustberg, Maryam B; Berger, Michael J

2015-11-01

To review palbociclib, a novel small-molecule inhibitor of cyclin-dependent kinases 4 and 6, and its current place in therapy for the treatment of hormone receptor (HMR)-positive, human epidermal growth factor receptor 2 (Her2)-negative advanced breast cancer. Four phase I trials, 2 phase II trials, and 1 phase III trial were identified from May 2004 to May 2015 using PubMed, American Society of Clinical Oncology (ASCO) abstracts, and European Society of Medical Oncology (ESMO) abstracts. In the first-line setting, the phase II PALbociclib: Ongoing trials in the Management of breast cAncer (PALOMA)-1 trial randomized patients to receive letrozole alone or letrozole plus palbociclib 125 mg daily for 3 weeks, followed by 1 week off, as initial therapy for advanced breast cancer. The investigator-assessed median progression-free survival (PFS) was 20. 2 months for the combination versus 10.2 months for letrozole alone (hazard ratio [HR] = 0.488; 95% CI = 0.319-0.748; 1-sided P = 0.0004). The ensuing Food and Drug Administration approval of palbociclib was given a "breakthrough therapy" designation, where preliminary evidence suggests substantial improvement over existing therapies for a serious or life-threatening disease. A confirmatory phase III trial, PALOMA-2, is under way. In patients who were previously treated with endocrine therapy for advanced breast cancer, the phase III PALOMA-3 trial randomized patients to fulvestrant plus palbociclib versus fulvestrant plus placebo. The investigator-assessed median PFS at the time of a preplanned analysis was 9.2 months with palbociclib-fulvestrant compared with 3.8 months with placebo-fulvestrant (HR = 0.42; 95% CI = 0.32-0.56; P < 0.001). Palbociclib, the first-in-class CDK4/6 inhibitor, significantly extended PFS in combination with endocrine therapy in the first and subsequent lines of treatment for HMR-positive, Her2-negative advanced breast cancer. © The Author(s) 2015.

Small Changes and Lasting Effects (SCALE) Trial: The Formation of a Weight Loss Behavioral Intervention Using EVOLVE

PubMed Central

Phillips-Caesar, Erica G.; Winston, Ginger; Peterson, Janey C.; Wansink, Brian; Devine, Carol M.; Kanna, Balavanketsh; Michelin, Walid; Wethington, Elaine; Wells, Martin; Hollenberg, James; Charlson, Mary E.

2015-01-01

Background Obesity is a major health problem that disproportionately affects Black and Hispanic adults. This paper presents the rationale and innovative design of a small change eating and physical activity intervention (SC) combined with a positive affect and self-affirmation (PA/SA) intervention versus the SC intervention alone for weight loss. Methods Using a mixed methods translational model (EVOLVE), we designed and tested a SC approach intervention in overweight and/ or obese African American and Hispanic adults. In Phase I, we explored participant’s values and beliefs about the small change approach. In Phase II, we tested and refined the intervention and then, in Phase III we conducted a RCT. Participants were randomized to the SC approach with PA/SA intervention vs. a SC approach alone for 12 months. The primary outcome was clinically significant weight loss at 12 months. Results Over 4.5 years a total of 574 participants (67 in Phase I, 102 in Phase II and 405 in Phase III) were enrolled. Phase I findings were used to create a workbook based on real life experiences about weight loss and to refine the small change eating strategies. Phase II results shaped the recruitment and retention strategy for the RCT, as well as the final intervention. The RCT results are currently under analysis. Conclusion The present study seeks to determine if a SC approach combined with a PA/SA intervention will result in greater weight loss at 12 months in Black and Hispanic adults compared to a SC approach alone. PMID:25633208

Motor Training Promotes Both Synaptic and Intrinsic Plasticity of Layer II/III Pyramidal Neurons in the Primary Motor Cortex

PubMed Central

Kida, Hiroyuki; Tsuda, Yasumasa; Ito, Nana; Yamamoto, Yui; Owada, Yuji; Kamiya, Yoshinori; Mitsushima, Dai

2016-01-01

Motor skill training induces structural plasticity at dendritic spines in the primary motor cortex (M1). To further analyze both synaptic and intrinsic plasticity in the layer II/III area of M1, we subjected rats to a rotor rod test and then prepared acute brain slices. Motor skill consistently improved within 2 days of training. Voltage clamp analysis showed significantly higher α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid/N-methyl-d-aspartate (AMPA/NMDA) ratios and miniature EPSC amplitudes in 1-day trained rats compared with untrained rats, suggesting increased postsynaptic AMPA receptors in the early phase of motor learning. Compared with untrained controls, 2-days trained rats showed significantly higher miniature EPSC amplitude and frequency. Paired-pulse analysis further demonstrated lower rates in 2-days trained rats, suggesting increased presynaptic glutamate release during the late phase of learning. One-day trained rats showed decreased miniature IPSC frequency and increased paired-pulse analysis of evoked IPSC, suggesting a transient decrease in presynaptic γ-aminobutyric acid (GABA) release. Moreover, current clamp analysis revealed lower resting membrane potential, higher spike threshold, and deeper afterhyperpolarization in 1-day trained rats—while 2-days trained rats showed higher membrane potential, suggesting dynamic changes in intrinsic properties. Our present results indicate dynamic changes in glutamatergic, GABAergic, and intrinsic plasticity in M1 layer II/III neurons after the motor training. PMID:27193420

Motor Training Promotes Both Synaptic and Intrinsic Plasticity of Layer II/III Pyramidal Neurons in the Primary Motor Cortex.

PubMed

Kida, Hiroyuki; Tsuda, Yasumasa; Ito, Nana; Yamamoto, Yui; Owada, Yuji; Kamiya, Yoshinori; Mitsushima, Dai

2016-08-01

Motor skill training induces structural plasticity at dendritic spines in the primary motor cortex (M1). To further analyze both synaptic and intrinsic plasticity in the layer II/III area of M1, we subjected rats to a rotor rod test and then prepared acute brain slices. Motor skill consistently improved within 2 days of training. Voltage clamp analysis showed significantly higher α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid/N-methyl-d-aspartate (AMPA/NMDA) ratios and miniature EPSC amplitudes in 1-day trained rats compared with untrained rats, suggesting increased postsynaptic AMPA receptors in the early phase of motor learning. Compared with untrained controls, 2-days trained rats showed significantly higher miniature EPSC amplitude and frequency. Paired-pulse analysis further demonstrated lower rates in 2-days trained rats, suggesting increased presynaptic glutamate release during the late phase of learning. One-day trained rats showed decreased miniature IPSC frequency and increased paired-pulse analysis of evoked IPSC, suggesting a transient decrease in presynaptic γ-aminobutyric acid (GABA) release. Moreover, current clamp analysis revealed lower resting membrane potential, higher spike threshold, and deeper afterhyperpolarization in 1-day trained rats-while 2-days trained rats showed higher membrane potential, suggesting dynamic changes in intrinsic properties. Our present results indicate dynamic changes in glutamatergic, GABAergic, and intrinsic plasticity in M1 layer II/III neurons after the motor training. © The Author 2016. Published by Oxford University Press.

Practice versus knowledge when it comes to pressure ulcer prevention.

PubMed

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

1997-09-01

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

Incorporation of zero valent iron nanoparticles in the matrix of cationic resin beads for the remediation of Cr(VI) contaminated waters.

PubMed

Toli, Aikaterini; Chalastara, Konstantina; Mystrioti, Christiana; Xenidis, Anthimos; Papassiopi, Nymphodora

2016-07-01

The objective of present study was to obtain the fixation of nano zero valent iron (nZVI) particles on a permeable matrix and evaluate the performance of this composite material for the removal of Cr(VI) from contaminated waters. The experiments were carried out using the cationic resin Dowex 50WX2 as porous support of the iron nanoparticles. The work was carried out in two phases. The first phase involved the fixation of nZVI on the resin matrix. The resin granules were initially mixed with a FeCl3 solution to obtain the adsorption of Fe(III). Then the Fe(III) loaded resin (RFe) was treated with polyphenol solutions to obtain the reduction of Fe(III) to the elemental state. Two polyphenol solutions were tested as reductants, i.e. green tea extract and gallic acid. Green tea was found to be inefficient, probably due to the relatively big size of the contained polyphenol molecules, but gallic acid molecules were able to reach adsorbed Fe(III) and reduce the cations to the elemental state. The second phase was focused on the investigation of Cr(VI) reduction kinetics using the nanoiron loaded resins (R-nFe). It was found that the reduction follows a kinetic law of first order with respect to Cr(VI) and to the embedded nanoiron. Compared to other similar products, this composite material was found to have comparable performance regarding reaction rates and higher degree of iron utilization. Namely the rate constant for the reduction of Cr(VI), in the presence of 1 mM nZVI, was equivalent to 1.4 h of half-life time at pH 3.2 and increased to 24 h at pH 8.5. The degree of iron utilization was as high as 0.8 mol of reduced Cr(VI) per mole of iron. It was also found that this composite material can be easily regenerated and reused for Cr(VI) reduction without significant loss of efficiency. Copyright © 2016 Elsevier Ltd. All rights reserved.

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.

Bioactivity of Epigallocatechin Gallate Nanoemulsions Evaluated in Mice Model.

PubMed

Koutelidakis, Antonios E; Argyri, Konstantina; Sevastou, Zoi; Lamprinaki, Dimitra; Panagopoulou, Elli; Paximada, Evi; Sali, Aggeliki; Papalazarou, Vassilis; Mallouchos, Athanasios; Evageliou, Vasiliki; Kostourou, Vasiliki; Mantala, Ioanna; Kapsokefalou, Maria

2017-09-01

The hypothesis that incorporation of epigallocatechin gallate (EGCG) into nanoemulsions may increase its bioactivity compared with EGCG aqueous solutions was examined in mice. After an in vitro study in a model system with stimulated gastrointestinal conditions, the following EGCG nanoemulsions were used in a mice experiment: Emulsion I: emulsion water in oil (W/O), which contained 0.23 mg/mL EGCG in aqueous phase; Emulsion II: emulsion oil in water (O/W), which contained 10% olive oil and 0.23 mg/mL esterified EGCG in fatty phase; and Emulsion III: emulsion O/W in water (W1/O/W2; 8:32:60), which contained 32% olive oil and 0.23 mg/mL EGCG in aqueous phase. After 2 h of mice administration by gavage with 0.1 mL of EGCG nanoemulsions, total antioxidant capacity (TAC) of plasma and some tissues (especially colon, jejunum, heart, spleen) was measured with Ferric-Reducing Antioxidant Power (FRAP) and Oxygen Radical Absorbance Capacity (ORAC) assays. No toxic effects were observed after administration of 0.23 mg/mL esterified EGCG in CD1 mouse strain. The study concluded that administration of mice with the three EGCG nanoemulsions did not increase their TAC in specific tissues, compared with an aqueous EGCG solution at the same concentration. Nevertheless, the esterified EGCG emulsion (Emulsion II) exerted an increase in mice plasma compared with aqueous EGCG and showed higher values of TAC in several tissues, compared with Emulsions I and III. EGCG nanoemulsions could be considered a useful method in plethora functional food applications, but further research is required for safer results.

Accelerated hypofractionated three-dimensional conformal radiation therapy (3 Gy/fraction) combined with concurrent chemotherapy for patients with unresectable stage III non-small cell lung cancer: preliminary results of an early terminated phase II trial.

PubMed

Ren, Xiao-Cang; Wang, Quan-Yu; Zhang, Rui; Chen, Xue-Ji; Wang, Na; Liu, Yue-E; Zong, Jie; Guo, Zhi-Jun; Wang, Dong-Ying; Lin, Qiang

2016-04-23

Increasing the biological effective dose (BED) of radiotherapy for non-small cell lung cancer (NSCLC) can increase local control rates and improve overall survival. Compared with conventional fractionated radiotherapy, accelerated hypofractionated radiotherapy can yield higher BED, shorten the total treatment time, and theoretically obtain better efficacy. However, currently, there is no optimal hypofractionated radiotherapy regimen. Based on phase I trial results, we performed this phase II trial to further evaluate the safety and preliminary efficacy of accelerated hypofractionated three-dimensional conformal radiation therapy(3-DCRT) combined with concurrent chemotherapy for patients with unresectable stage III NSCLC. Patients with previously untreated unresectable stage III NSCLC received 3-DCRT with a total dose of 69 Gy, delivered at 3 Gy per fraction, once daily, five fractions per week, completed within 4.6 weeks. At the same time, platinum doublet chemotherapy was applied. After 12 patients were enrolled in the group, the trial was terminated early. There were five cases of grade III radiation esophagitis, of which four cases completed the radiation doses of 51 Gy, 51 Gy, 54 Gy, and 66 Gy, and one case had 16 days of radiation interruption. The incidence of grade III acute esophagitis in patients receiving an irradiation dose per fraction ≥2.7 Gy on the esophagus was 83.3% (5/6). The incidence of symptomatic grade III radiation pneumonitis among the seven patients who completed 69 Gy according to the plan was 28.6% (2/7). The median local control (LC) and overall survival (OS) were not achieved; the 1-year LC rate was 59.3%, and the 1-year OS rate was 78.6%. For unresectable stage III NSCLC, the accelerated hypofractionated radiotherapy with a total dose of 69 Gy (3 Gy/f) combined with concurrent chemotherapy might result in severe radiation esophagitis and pneumonitis to severely affect the completion of the radiotherapy. Therefore, we considered that this regimen was infeasible. During the hypofractionated radiotherapy with concurrent chemotherapy, the irradiation dose per fraction to esophagus should be lower than 2.7 Gy. Further studies should be performed using esophageal tolerance as a metric in dose escalation protocols. NCT02720614, the date of registration: March 23, 2016.

Quasi-elastic (QENS) and inelastic neutron scattering (INS) on hexamethylbenzene

NASA Astrophysics Data System (ADS)

Krawczyk, J.; Mayer, J.; Natkaniec, I.; Nowina Konopka, M.; Pawlukojć; Steinsvoll, O.; Janik, J. A.

2005-05-01

The Quasi-elastic Neutron scattering (QENS) spectra of polycrystalline hexamethylbenzene (HMB) were measured for temperatures from 10 K to room temperature (phase III and phase II) for momentum transfer 1.9 Å -1. The Inelastic Neutron scattering (INS) and QENS spectra for momentum transfer 0.5-2.9 Å -1 were measured at T=20, 100 and 130 K for energy transfer up to 200 meV. The low-resolution diffraction patterns, used as the phase indicator, were also obtained. In the phase III (below 117 K), we see practically no quasi-elastic broadening. In phase II, the broadening changes with the temperature are in good agreement with the Arrhenius law. The estimated activation barrier to reorientation is 6 kJ/mol. The fitted mean time between instantaneous 120° jumps of CH 3 groups changes from 10 -11 s at T=130 K to 2×10 -13 s at room temperature. On the basis of EISF versus momentum transfer dependency it is hardly possible to decide what is the geometry of the reorientation. Both reorientation of the CH 3 groups around the three-fold symmetry axis and reorientation of the whole molecule around the six-fold symmetry axis of the benzene ring could describe our results, the former being more probable. The measured INS spectra are compared with the quantum chemical ab initio calculations performed for an isolated HMB molecule.

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.

78 FR 18325 - Defense Transportation Regulation, Part IV

Federal Register 2010, 2011, 2012, 2013, 2014

2013-03-26

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

76 FR 36095 - Defense Transportation Regulation, Part IV

Federal Register 2010, 2011, 2012, 2013, 2014

2011-06-21

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

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

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

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

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

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

Federal Register 2010, 2011, 2012, 2013, 2014

2011-08-29

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

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

Federal Register 2010, 2011, 2012, 2013, 2014

2011-06-08

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

Seamless Phase IIa/IIb and enhanced dose-finding adaptive design.

PubMed

Yuan, Jiacheng; Pang, Herbert; Tong, Tiejun; Xi, Dong; Guo, Wenzhao; Mesenbrink, Peter

2016-01-01

In drug development, when the drug class has a relatively well-defined path to regulatory approval and the enrollment is slow with certain patient populations, one may want to consider combining studies of different phases. This article considers combining a proof of concept (POC) study and a dose-finding (DF) study with a control treatment. Conventional DF study designs sometimes are not efficient, or do not have a high probability to find the optimal dose(s) for Phase III trials. This article seeks more efficient DF strategies that allow the economical testing of more doses. Hypothetical examples are simulated to compare the proposed adaptive design vs. the conventional design based on different models of the overall quantitative representation of efficacy, safety, and tolerability. The results show that the proposed adaptive design tests more active doses with higher power and comparable or smaller sample size in a shorter overall study duration for POC and DF, compared with a conventional design.

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.

Phase III Open-Label Randomized Study of Eribulin Mesylate Versus Capecitabine in Patients With Locally Advanced or Metastatic Breast Cancer Previously Treated With an Anthracycline and a Taxane

PubMed Central

Kaufman, Peter A.; Awada, Ahmad; Twelves, Chris; Yelle, Louise; Perez, Edith A.; Velikova, Galina; Olivo, Martin S.; He, Yi; Dutcus, Corina E.; Cortes, Javier

2015-01-01

Purpose This phase III randomized trial (ClinicalTrials.gov identifier: NCT00337103) compared eribulin with capecitabine in patients with locally advanced or metastatic breast cancer (MBC). Patients and Methods Women with MBC who had received prior anthracycline- and taxane-based therapy were randomly assigned to receive eribulin or capecitabine as their first-, second-, or third-line chemotherapy for advanced/metastatic disease. Stratification factors were human epidermal growth factor receptor-2 (HER2) status and geographic region. Coprimary end points were overall survival (OS) and progression-free survival (PFS). Results Median OS times for eribulin (n = 554) and capecitabine (n = 548) were 15.9 and 14.5 months, respectively (hazard ratio [HR], 0.88; 95% CI, 0.77 to 1.00; P = .056). Median PFS times for eribulin and capecitabine were 4.1 and 4.2 months, respectively (HR, 1.08; 95% CI, 0.93 to 1.25; P = .30). Objective response rates were 11.0% for eribulin and 11.5% for capecitabine. Global health status and overall quality-of-life scores over time were similar in the treatment arms. Both treatments had manageable safety profiles consistent with their known adverse effects; most adverse events were grade 1 or 2. Conclusion In this phase III study, eribulin was not shown to be superior to capecitabine with regard to OS or PFS. PMID:25605862

Efficacy and safety of teneligliptin, a novel dipeptidyl peptidase-4 inhibitor, in Korean patients with type 2 diabetes mellitus: a 24-week multicentre, randomized, double-blind, placebo-controlled phase III trial.

PubMed

Hong, S; Park, C-Y; Han, K A; Chung, C H; Ku, B J; Jang, H C; Ahn, C W; Lee, M-K; Moon, M K; Son, H S; Lee, C B; Cho, Y-W; Park, S-W

2016-05-01

We assessed the 24-week efficacy and safety of teneligliptin, a novel dipeptidyl peptidase-4 inhibitor, in Korean patients with type 2 diabetes mellitus (T2DM) that was inadequately controlled with diet and exercise. The present study was designed as a multicentre, randomized, double-blind, placebo-controlled, parallel-group, phase III study. Patients (n = 142) were randomized 2 : 1 into two different treatment groups as follows: 99 received teneligliptin (20 mg) and 43 received placebo. The primary endpoint was change in glycated haemoglobin (HbA1c) level from baseline to week 24. Teneligliptin significantly reduced the HbA1c level from baseline compared with placebo after 24 weeks. At week 24, the differences between changes in HbA1c and fasting plasma glucose (FBG) in the teneligliptin and placebo groups were -0.94% [least-squares (LS) mean -1.22, -0.65] and -1.21 mmol/l (-1.72, -0.70), respectively (all p < 0.001). The incidence of hypoglycaemia and adverse events were not significantly different between the two groups. This phase III, randomized, placebo-controlled study provides evidence of the safety and efficacy of 24 weeks of treatment with teneligliptin as a monotherapy in Korean patients with T2DM. © 2016 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.

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.

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

PubMed

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

2013-07-01

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

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.

Specific CDK4/6 inhibition in breast cancer: a systematic review of current clinical evidence

PubMed Central

Polk, Anne; Kolmos, Ida Lykke; Kümler, Iben; Nielsen, Dorte Lisbeth

2016-01-01

Background Loss of cell cycle control is a hallmark of cancer, and aberrations in the cyclin-dependent kinase-retinoblastoma (CDK-Rb) pathway are common in breast cancer (BC). Consequently, inhibition of this pathway is an attractive therapeutic strategy. The present review addresses efficacy and toxicity of CDK4/6 inhibition in BC. Methods A literature search was carried out using PubMed and EMBASE; data reported at international meetings and clinicaltrials.gov were included. Results Three specific CDK4/6 inhibitors palbociclib, abemaciclib and ribociclib are tested in clinical trials. A randomised phase II trial of palbociclib plus letrozole versus letrozole and a phase III of palbociclib plus fulvestrant versus fulvestrant showed significantly increased progression-free survival when compared with endocrine therapy alone in first-line and second-line treatment for advanced hormone receptor-positive HER2-negative BC. At the moment several phase III studies are ongoing with all three CDK4/6 inhibitors in hormone receptor-positive HER2-negative BC as well as other subtypes of BC. The predominant toxicity of agents was limited neutropenia. Other common adverse events were infections, fatigue and gastrointestinal toxicity. The toxicities seemed manageable. Yet data are too limited to differentiate between the compounds. Retinoblastoma protein (Rb) is considered a promising biomarker. Conclusion CDK4/6 inhibition might represent a substantial advance for patients with hormone receptor-positive HER2-negative BC. Results must be confirmed in phase III trials before any firm conclusions can be made regarding the future influence of CDK4/6 inhibition. There is an urgent need for prospective biomarker-driven trials to identify patients for whom CDK4/6 inhibition is cost-effective. PMID:28848657

Kinetics of methane production and biodegradation of linear alkylbenzene sulfonate from laundry wastewater.

PubMed

Motteran, Fabrício; Braga, Juliana K; Silva, Edson L; Varesche, Maria Bernadete A

2016-12-05

This study evaluates the kinetics of methane production and degradation of standard linear alkylbenzene sulfonate (LAS) (50 ± 3.5 mg/L) and LAS from laundry wastewater (85 ± 2.1 mg/L) in anaerobic batch reactors at 30°C with different sources of inoculum. The inocula were obtained by auto-fermentation (AFM) and UASB reactors from wastewater treatment of poultry slaughterhouse (SGH), swine production (SWT) and wastewater treatment thermophilic of sugarcane industry (THR). The study was divided into three phases: synthetic substrate (Phase I), standard LAS (Phase II) and LAS from laundry wastewater (Phase III). For SGH, the highest values for cumulative methane productions (1,844.8 ± 149 µmol-Phase II), methane production rate (70.8 ± 88 µmol/h-Phase II and 4.01 ± 07 µmol/h-Phase III) were observed. The use of thermophilic biomass (THR) incubated at 30°C was not favorable for methane production and LAS biodegradation, but the highest kinetic coefficient degradation (k 1 app ) was obtained for LAS (0.33 ± 0.3 h) compared with mesophilic biomass (SGH and SWT) (0.13 ± 0.02 h). Therefore, both LAS sources influenced the kinetics of methane production and organic matter degradation. For SGH, inoculum obtained the highest LAS degradation. In the SGH inoculum sequenced by MiSeq-Illumina was identified genera (VadinCA02, Candidatus Cloacamonas, VadinHB04, PD-UASB-13) related to degrade toxic compounds. Therefore, it recommended the reactor mesophilic inoculum UASB (SGH) for the LAS degradation.

Computation-based virtual screening for designing novel antimalarial drugs by targeting falcipain-III: a structure-based drug designing approach.

PubMed

Kesharwani, Rajesh Kumar; Singh, Durg Vijay; Misra, Krishna

2013-01-01

Cysteine proteases (falcipains), a papain-family of enzymes of Plasmodium falciparum, are responsible for haemoglobin degradation and thus necessary for its survival during asexual life cycle phase inside the human red blood cells while remaining non-functional for the human body. Therefore, these can act as potential targets for designing antimalarial drugs. The P. falciparum cysteine proteases, falcipain-II and falcipain- III are the enzymes which initiate the haemoglobin degradation, therefore, have been selected as targets. In the present study, we have designed new leupeptin analogues and subjected to virtual screening using Glide at the active site cavity of falcipain-II and falcipain-III to select the best docked analogues on the basis of Glide score and also compare with the result of AutoDock. The proposed analogues can be synthesized and tested in vivo as future potent antimalarial drugs. Protein falcipain-II and falcipain-III together with bounds inhibitors epoxysuccinate E64 (E64) and leupeptin respectively were retrieved from protein data bank (PDB) and latter leupeptin was used as lead molecule to design new analogues by using Ligbuilder software and refined the molecules on the basis of Lipinski rule of five and fitness score parameters. All the designed leupeptin analogues were screened via docking simulation at the active site cavity of falcipain-II and falcipain-III by using Glide software and AutoDock. The 104 new leupeptin-based antimalarial ligands were designed using structure-based drug designing approach with the help of Ligbuilder and subjected for virtual screening via docking simulation method against falcipain-II and falcipain-III receptor proteins. The Glide docking results suggest that the ligands namely result_037 shows good binding and other two, result_044 and result_042 show nearly similar binding than naturally occurring PDB bound ligand E64 against falcipain-II and in case of falcipain-III, 15 designed leupeptin analogues having better binding affinity compared to the PDB bound inhibitor of falcipain-III. The docking simulation results of falcipain-III with designed leupeptin analogues using Glide compared with AutoDock and find 80% similarity as better binder than leupeptin. These results further highlight new leupeptin analogues as promising future inhibitors for chemotherapeutic prevention of malaria. The result of Glide for falcipain-III has been compared with the result of AutoDock and finds very less differences in their order of binding affinity. Although there are no extra hydrogen bonds, however, equal number of hydrogen bonds with variable strength as compared to leupeptin along with the enhanced hydrophobic and electrostatic interactions in case of analogues supports our study that it holds the ligand molecules strongly within the receptor. The comparative e-pharmacophoric study also suggests and supports our predictions regarding the minimum features required in ligand molecule to behave as falcipain- III inhibitors and is also helpful in screening the large database as future antimalarial inhibitors.

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.

Performance evaluation of two black nickel and two black chrome solar collectors

NASA Technical Reports Server (NTRS)

Losey, R.

1977-01-01

The test program was based on the evaluation of four unique solar collectors described below: (1) black nickel collector surface with a desiccant drying bed, (2) black nickel collector surface without a desiccant drying bed, (3) black chrome collector surface with a dessicant drying bed, and (4) black chrome collector surface without a desiccant drying bed. The test program included three distinct phases: Initial performance evaluation, natural environmental aging, and post-aging performance evaluation. Results of Phase III testing conclusively indicated a higher normalized efficiency for Black Chrome surfaces when compared to Black Nickel.

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.

Effect of high fluorine on the cell cycle and apoptosis of renal cells in chickens.

PubMed

Bai, Caimin; Chen, Tao; Cui, Yun; Gong, Tao; Peng, Xi; Cui, Heng-Min

2010-12-01

The experiment was conducted with the objective of evaluating the effect of dietary high fluorine (F) on cell cycle and apoptosis of kidney in chickens by the methods of flow cytometry. Three hundred 1-day-old Avian broilers were divided into four groups and fed on control diet (F 23 mg/kg) and high F diets (400 mg/kg, high F group I; 800 mg/kg, high F group II; 1,200 mg/kg, high F group III) for 6 weeks. As tested by flow cytometry, the percentage of renal cell apoptosis was increased with increasing of dietary F, and it obviously rose in three high F groups when compared with that of control group. Renal cells in G(0)/G(1) phase were much higher, and renal cells in S phase, G(2)+M phase, and proliferation index value were much lower in high F groups I, II, and III than in control group. The results showed that excess dietary F in the range of 400-1,200 mg/kg caused G(0)/G(1) arrest and increased cellular apoptosis in the kidney, which might finally interfere with the excretion and retention of fluoride in chickens.

Evolution of a phase separated gravity independent bioreactor

NASA Technical Reports Server (NTRS)

Villeneuve, Peter E.; Dunlop, Eric H.

1992-01-01

The evolution of a phase-separated gravity-independent bioreactor is described. The initial prototype, a zero head-space manifold silicone membrane based reactor, maintained large diffusional resistances. Obtaining oxygen transfer rates needed to support carbon-recycling aerobic microbes is impossible if large resistances are maintained. Next generation designs (Mark I and II) mimic heat exchanger design to promote turbulence at the tubing-liquid interface, thereby reducing liquid and gas side diffusional resistances. While oxygen transfer rates increased by a factor of ten, liquid channeling prevented further increases. To overcome these problems, a Mark III reactor was developed which maintains inverted phases, i.e., media flows inside the silicone tubing, oxygen gas is applied external to the tubing. This enhances design through changes in gas side driving force concentration and liquid side turbulence levels. Combining an applied external pressure of 4 atm with increased Reynolds numbers resulted in oxygen transfer intensities of 232 mmol O2/l per hr (1000 times greater than the first prototype and comparable to a conventional fermenter). A 1.0 liter Mark III reactor can potentially deliver oxygen supplies necessary to support cell cultures needed to recycle a 10-astronaut carbon load continuously.

A phase II trial for the efficacy of physiotherapy intervention for early-onset hip osteoarthritis: study protocol for a randomised controlled trial.

PubMed

Kemp, Joanne L; Moore, Kate; Fransen, Marlene; Russell, Trevor G; Crossley, Kay M

2015-01-27

Early-onset hip osteoarthritis is commonly seen in people undergoing hip arthroscopy and is associated with increased pain, reduced ability to participate in physical activity, reduced quality of life and reduced range of motion and muscle strength. Despite this, the efficacy of non-surgical interventions such as exercise therapies remains unknown. The primary aim is to establish the feasibility of a phase III randomised controlled trial investigating a targeted physiotherapy intervention for people with early-onset hip osteoarthritis. The secondary aims are to determine the size of treatment effects of a physiotherapy intervention, targeted to improve hip joint range and hip-related symptoms in early-onset hip osteoarthritis following hip arthroscopy, compared to a health-education control. This protocol describes a randomised, assessor- and participant-blind, controlled clinical trial. We will include 20 participants who are (i) aged between 18 and 50 years; (ii) have undergone hip arthroscopy during the past six to 12 months; (iii) have early-onset hip osteoarthritis (defined as chondrolabral pathology) at the time of hip arthroscopy; and (iv) experience hip-related pain during activities. Primary outcome will be the feasibility of a phase III clinical trial. Secondary outcomes will be (i) perceived global change score; (ii) hip-related symptoms (measured using the Hip disability and Osteoarthritis Outcome Score (HOOS) pain subscale, activity subscale, and sport and recreation subscale); (iii) hip quality of life (measured using the HOOS quality of life subscale and International Hip Outcome tool; (iv) hip muscle strength and (v) hip range of motion. The physiotherapy intervention is semi-standardised, including joint and soft tissue mobilisation and stretching, hip and trunk muscle retraining and functional and activity-specific retraining and education. The control intervention encompasses individualised health education, with the same frequency and duration as the intervention. The trial primary end-point is the conclusion of the 12-week intervention, and follow-up measures will be collected at the 12-week post-baseline assessment. The findings of this study will provide guidance regarding the feasibility of a full-scale phase III randomised controlled trial, prior to its undertaking. The trial protocol was registered with the Australian Clinical Trials Registry (number: 12614000426684 ) on 17 April 2014.

Microbial exudate promoted dissolution and transformation of chromium containing minerals

NASA Astrophysics Data System (ADS)

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

2015-12-01

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

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

PubMed

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

2012-12-05

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

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

NASA Astrophysics Data System (ADS)

Takemura, T.; Chin, M.

2014-12-01

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

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

PubMed Central

2012-01-01

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

New developments in chemotherapy of advanced breast cancer.

PubMed

Lebwohl, D E; Canetta, R

1999-01-01

Anthracyclines and taxanes are the two most active classes of chemotherapy for the treatment of advanced breast cancer. Recent studies have investigated combination therapy including doxorubicin (Dox) and paclitaxel. The efficacy of this combination has been established in a phase III study conducted by ECOG, comparing Dox/paclitaxel versus Dox versus paclitaxel. The combination is superior to Dox or paclitaxel with respect to response rate and time to disease progression, indicating that the combination provides a new standard for the first line treatment of metastatic breast cancer [1]. Phase II studies using higher doses of Dox and using shorter infusions of paclitaxel have suggested the combination can be further optimized; Gianni reported a 94% objective response rate using Dox 60 mg/m2 followed by paclitaxel 175 mg/m2 given over three hours [2]. The more active regimens are associated with enhanced cardiotoxicity; this toxicity can be avoided, however, by limiting the exposure to doxorubicin. The newer regimens have now been moved into phase III studies. Future progress for this disease will depend on the introduction of new agents. Two novel drugs are currently being investigated in randomised phase III trials as potentiators of Dox and/or paclitaxel. One is a monoclonal antibody from Genentech (Herceptin, trastuzumab) directed at the HER-2/neu oncogene, which is overexpressed in > 25% of breast cancers [3]. Recent results indicate that Herceptin in combination with paclitaxel (or with a Dox plus cyclophosphamide regimen) induces a higher response rate (RR) and prolongs the time to disease progression when compared to chemotherapy alone. The second agent N,N-diethyl-2[4-(phenylmethyl)-phenoxy] ethanamine.HCl (DPPE, BMS-217380-01), when combined with Dox, was associated with a higher RR than previously observed with Dox alone [4]. A randomized trial of Dox versus Dox plus DPPE is ongoing. The possible mechanisms underlying chemo-potentiation by these agents are discussed. As new anthracycline/taxane combinations establish themselves in earlier stages of the disease, the need for effective, non-cross resistant salvage regimens will emerge.

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.

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).

Estimates of general combining ability in Hevea breeding at the Rubber Research Institute of Malaysia : I. Phases II and III A.

PubMed

Tan, H

1977-01-01

Estimates of general combining ability of parents for yield and girth obtained separately from seedlings and their corresponding clonal families in Phases II and IIIA of the RRIM breeding programme are compared. A highly significant positive correlation (r = 0.71***) is found between GCA estimates from seedling and clonal families for yield in Phase IIIA, but not in Phase II (r = -0.03(NS)) nor for girth (r= -0.27(NS)) in Phase IIIA. The correlations for Phase II yield and Phase IIIA girth, however, improve when the GCA estimates based on small sample size or reversed rankings are excluded.When the best selections (based on present clonal and seedling information) are compared, all five of the parents top-ranking for yield are common in Phase IIIA but only two parents are common for yield and girth in Phases II and IIIA respectively. However, only one parent for yield in Phase II and two parents for girth in Phase IIIA would, if selected on clonal performance, have been omitted from the top ranking selections made by previous workers using seedling information.These findings, therefore, justify the choice of parents based on GCA estimates for yield obtained from seedling performance. Similar justification cannot be offered for girth, for which analysis is confounded by uninterpretable site and seasonal effects.

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.

Assessing Compliance With Mercaptopurine Treatment in Younger Patients With Acute Lymphoblastic Leukemia in First Remission | Division of Cancer Prevention

Cancer.gov

This randomized phase III trial studies compliance to a mercaptopurine treatment intervention compared to standard of care in younger patients with acute lymphoblastic leukemia in remission. Assessing ways to help patients who have acute lymphoblastic leukemia to take their medications as prescribed may help them in taking their medications more consistently and may improve

Antiemetic Therapy With or Without Olanzapine in Preventing Chemotherapy-Induced Nausea and Vomiting in Patients With Cancer Receiving Highly Emetogenic Chemotherapy | Division of Cancer Prevention

Cancer.gov

This randomized phase III trial studies antiemetic therapy with olanzapine to see how well they work compared to antiemetic therapy alone in preventing chemotherapy-induced nausea and vomiting in patients with cancer receiving highly emetogenic (causes vomiting) chemotherapy. Antiemetic drugs, such as palonosetron hydrochloride, ondansetron, and granisetron hydrochloride, may

COMPARE CPM-RMI Trial: Intramyocardial Transplantation of Autologous Bone Marrow-Derived CD133+ Cells and MNCs during CABG in Patients with Recent MI: A Phase II/III, Multicenter, Placebo-Controlled, Randomized, Double-Blind Clinical Trial.

PubMed

Naseri, Mohammad Hassan; Madani, Hoda; Ahmadi Tafti, Seyed Hossein; Moshkani Farahani, Maryam; Kazemi Saleh, Davood; Hosseinnejad, Hossein; Hosseini, Saeid; Hekmat, Sepideh; Hossein Ahmadi, Zargham; Dehghani, Majid; Saadat, Alireza; Mardpour, Soura; Hosseini, Seyedeh Esmat; Esmaeilzadeh, Maryam; Sadeghian, Hakimeh; Bahoush, Gholamreza; Bassi, Ali; Amin, Ahmad; Fazeli, Roghayeh; Sharafi, Yaser; Arab, Leila; Movahhed, Mansour; Davaran, Saeid; Ramezanzadeh, Narges; Kouhkan, Azam; Hezavehei, Ali; Namiri, Mehrnaz; Kashfi, Fahimeh; Akhlaghi, Ali; Sotoodehnejadnematalahi, Fattah; Vosough Dizaji, Ahmad; Gourabi, Hamid; Syedi, Naeema; Shahverdi, Abdol Hosein; Baharvand, Hossein; Aghdami, Nasser

2018-10-01

This article published in Cell J (Yakhteh), Vol 20, No 2, Jul-Sep 2018, on pages 267-277, four affiliations (1, 4, 5, and 10) were changed based on authors request. Copyright© by Royan Institute. All rights reserved.

Comparative pharmacokinetics and bioavailability of albendazole sulfoxide in sheep and goats, and dose-dependent plasma disposition in goats.

PubMed

Aksit, Dilek; Yalinkilinc, Hande Sultan; Sekkin, Selim; Boyacioğlu, Murat; Cirak, Veli Yilgor; Ayaz, Erol; Gokbulut, Cengiz

2015-05-27

The aims of this study were to compare the pharmacokinetics of albendazole sulfoxide (ABZ-SO, ricobendazole) in goats and sheep at a dose of 5 g/kg bodyweight (BW), after intravenous (IV) and subcutaneous (SC) administrations, and to investigate the effects of increased doses (10 and 15 mg/kg BW) on the plasma disposition of ABZ-SO in goats following SC administration. A total of 16 goats (Capra aegagrus hircus, eight males and eight females) and 8 sheep (Ovis aries, four males and four females) 12-16 months old and weighing 20-32 kg, were used. The study was designed according to two-phase crossover study protocol. In Phase-1, eight sheep were assigned as Group I and 16 goats were allocated into two groups (Group II and Group III). ABZ-SO was applied to Group I (sheep) and Group II (goats) animals subcutaneously, and to Group III (goats) animals intravenously, all at a dose rate of 5 mg/kg BW. In Phase-2, the sheep in the Group I received ABZ-SO intravenously in a dose of 5 mg/kg BW; the goats in Group II and Group III received ABZ-SO subcutaneously at a dose of 10 mg/kg and 15 mg/kg BW, respectively. Blood samples were collected from the jugular vein at different times between 1 and 120 h after drug administrations. The plasma concentrations of ABZ-SO and its metabolites were analysed by high performance liquid chromatography. In goats, the area under the curve, terminal half-life and plasma persistence of ABZ-SO were significantly smaller and shorter, respectively, compared with those observed in sheep following both IV and SC administrations at a dose of 5 mg/kg BW. On the other side, dose-dependent plasma dispositions of ABZ-SO were observed following SC administration at increased doses (10 and 15 mg/kg) in goats. Consequently, ABZ-SO might be used at higher doses to provide higher plasma concentration and thus to achieve greater efficacy against the target parasites.

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.

Periphyton and abiotic factors influencing arsenic speciation in aquatic environments: Periphyton alters arsenic speciation

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

Lopez, Adeline R.; Silva, Silmara Costa; Webb, Samuel M.

Benthic periphytic biofilms are important food sources at the base of aquatic ecosystems. These biofilms also sit at the interface of oxic waters and hypoxic sediments, and can be influenced by or influence trace element speciation. In the present study, we compared arsenic (As) enrichment in periphyton exposed to arsenate (As[V]) or arsenite (As[III]) (20 μg/L, static renewal, 7 d), and we found similar accumulation patterns of total As (101 ± 27 and 88 ± 22mgkg -1 dry wt, respectively). Periphyton As was 6281- and 6684-fold higher than their aqueous exposures and occurred primarily as As(V). When these biofilms weremore » fed to larval mayflies, similar total As tissue concentrations (13.9 and 14.6mgkg -1 dry wt, respectively) were observed, revealing significant biodilution (~10% of their dietary concentrations). Finally, we investigated the influence of aeration and periphyton presence on As speciation in solutions and solid phases treated with As(III). Predominantly As(III) solutions were slowly oxidized over a 7-d time period, in the absence of periphyton, and aeration did not strongly affect oxidation rates. However, in the presence of periphyton, solution and solid-phase analyses (by microscale x-ray absorption spectroscopy) showed rapid As(III) oxidation to As(V) and an increasing proportion of organo-As forming over time. Thus periphyton plays several roles in As environmental behavior: 1) decreasing total dissolved As concentrations via abiotic and biotic accumulation, 2) rapidly oxidizing As(III) to As(V), 3) effluxing organo-As forms into solution, and 4) limiting trophic transfer to aquatic grazers.« less

Periphyton and abiotic factors influencing arsenic speciation in aquatic environments: Periphyton alters arsenic speciation

DOE PAGES

Lopez, Adeline R.; Silva, Silmara Costa; Webb, Samuel M.; ...

2017-11-02

Benthic periphytic biofilms are important food sources at the base of aquatic ecosystems. These biofilms also sit at the interface of oxic waters and hypoxic sediments, and can be influenced by or influence trace element speciation. In the present study, we compared arsenic (As) enrichment in periphyton exposed to arsenate (As[V]) or arsenite (As[III]) (20 μg/L, static renewal, 7 d), and we found similar accumulation patterns of total As (101 ± 27 and 88 ± 22mgkg -1 dry wt, respectively). Periphyton As was 6281- and 6684-fold higher than their aqueous exposures and occurred primarily as As(V). When these biofilms weremore » fed to larval mayflies, similar total As tissue concentrations (13.9 and 14.6mgkg -1 dry wt, respectively) were observed, revealing significant biodilution (~10% of their dietary concentrations). Finally, we investigated the influence of aeration and periphyton presence on As speciation in solutions and solid phases treated with As(III). Predominantly As(III) solutions were slowly oxidized over a 7-d time period, in the absence of periphyton, and aeration did not strongly affect oxidation rates. However, in the presence of periphyton, solution and solid-phase analyses (by microscale x-ray absorption spectroscopy) showed rapid As(III) oxidation to As(V) and an increasing proportion of organo-As forming over time. Thus periphyton plays several roles in As environmental behavior: 1) decreasing total dissolved As concentrations via abiotic and biotic accumulation, 2) rapidly oxidizing As(III) to As(V), 3) effluxing organo-As forms into solution, and 4) limiting trophic transfer to aquatic grazers.« less

Mitochondrial function in skeletal muscle of patients with protracted critical illness and ICU-acquired weakness.

PubMed

Jiroutková, Kateřina; Krajčová, Adéla; Ziak, Jakub; Fric, Michal; Waldauf, Petr; Džupa, Valér; Gojda, Jan; Němcova-Fürstová, Vlasta; Kovář, Jan; Elkalaf, Moustafa; Trnka, Jan; Duška, František

2015-12-24

Mitochondrial damage occurs in the acute phase of critical illness, followed by activation of mitochondrial biogenesis in survivors. It has been hypothesized that bioenergetics failure of skeletal muscle may contribute to the development of ICU-acquired weakness. The aim of the present study was to determine whether mitochondrial dysfunction persists until protracted phase of critical illness. In this single-centre controlled-cohort ex vivo proof-of-concept pilot study, we obtained vastus lateralis biopsies from ventilated patients with ICU-acquired weakness (n = 8) and from age and sex-matched metabolically healthy controls (n = 8). Mitochondrial functional indices were measured in cytosolic context by high-resolution respirometry in tissue homogenates, activities of respiratory complexes by spectrophotometry and individual functional capacities were correlated with concentrations of electron transport chain key subunits from respiratory complexes II, III, IV and V measured by western blot. The ability of aerobic ATP synthesis (OXPHOS) was reduced to ~54% in ICU patients (p<0.01), in correlation with the depletion of complexes III (~38% of control, p = 0.02) and IV (~26% of controls, p<0.01) and without signs of mitochondrial uncoupling. When mitochondrial functional indices were adjusted to citrate synthase activity, OXPHOS and the activity of complexes I and IV were not different, whilst the activities of complexes II and III were increased in ICU patients 3-fold (p<0.01) respectively 2-fold (p<0.01). Compared to healthy controls, in ICU patients we have demonstrated a ~50% reduction of the ability of skeletal muscle to synthetize ATP in mitochondria. We found a depletion of complex III and IV concentrations and relative increases in functional capacities of complex II and glycerol-3-phosphate dehydrogenase/complex III.

Assessing the robustness of passive scattering proton therapy with regard to local recurrence in stage III non-small cell lung cancer: a secondary analysis of a phase II trial.

PubMed

Zhu, Zhengfei; Liu, Wei; Gillin, Michael; Gomez, Daniel R; Komaki, Ritsuko; Cox, James D; Mohan, Radhe; Chang, Joe Y

2014-05-06

We assessed the robustness of passive scattering proton therapy (PSPT) plans for patients in a phase II trial of PSPT for stage III non-small cell lung cancer (NSCLC) by using the worst-case scenario method, and compared the worst-case dose distributions with the appearance of locally recurrent lesions. Worst-case dose distributions were generated for each of 9 patients who experienced recurrence after concurrent chemotherapy and PSPT to 74 Gy(RBE) for stage III NSCLC by simulating and incorporating uncertainties associated with set-up, respiration-induced organ motion, and proton range in the planning process. The worst-case CT scans were then fused with the positron emission tomography (PET) scans to locate the recurrence. Although the volumes enclosed by the prescription isodose lines in the worst-case dose distributions were consistently smaller than enclosed volumes in the nominal plans, the target dose coverage was not significantly affected: only one patient had a recurrence outside the prescription isodose lines in the worst-case plan. PSPT is a relatively robust technique. Local recurrence was not associated with target underdosage resulting from estimated uncertainties in 8 of 9 cases.

Anal Cancer: An Examination of Radiotherapy Strategies

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

Glynne-Jones, Rob; Lim, Faye

2011-04-01

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

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

Noel, Donna

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

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.

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.

Saxagliptin for the treatment of type 2 diabetes mellitus: assessing cardiovascular data

PubMed Central

2012-01-01

Patients with type 2 diabetes mellitus (T2DM) are at high risk for cardiovascular (CV) disease; however, conclusive evidence that glycemic control leads to improved cardiovascular outcomes is lacking. Saxagliptin is a potent, selective dipeptidyl peptidase-4 inhibitor approved as an adjunct to diet and exercise to improve glycemic control in adults with T2DM. Saxagliptin was evaluated in a series of phase III trials as monotherapy; add-on therapy to metformin, a sulfonylurea, or a thiazolidinedione; and as initial therapy in combination with metformin. Saxagliptin consistently improved glycemic control (as reflected by significant decreases in glycated hemoglobin, fasting plasma glucose, and postprandial glucose compared with controls) and was generally well tolerated. In these analyses, saxagliptin had clinically neutral effects on body weight, blood pressure, lipid levels, and other markers of CV risk compared with controls. A retrospective meta-analysis of 8 phase II and phase III trials found no evidence that saxagliptin increases CV risk in patients with T2DM (Cox proportional hazard ratio, 0.43; 95% CI, 0.23-0.80 for major adverse cardiovascular events retrospectively adjudicated). Instead, it raised the hypothesis that saxagliptin may reduce the risk of major adverse CV events. A long-term CV outcome trial, Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus-THrombolysis in Myocardial Infarction 53 (SAVOR-TIMI 53) is currently ongoing to determine whether saxagliptin reduces CV risk in T2DM. PMID:22248301

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

Transdermal buprenorphine in the treatment of chronic pain: results of a phase III, multicenter, randomized, double-blind, placebo-controlled study.

PubMed

Sorge, Jürgen; Sittl, Reinhard

2004-11-01

Buprenorphine, a potent opioid analgesic, has been available in parenteral and oral or sublingual(SL) formulations for >25 years. In 2001, the buprenorphine transdermal delivery system (TES) was introduced at 3 release rates (35, 52.5, and 70 microg/h) for the treatment of chronic cancer and noncancer pain. This study compared the analgesic efficacy and tolerability of buprenorphine TES at a release rate of 35 microg/h with those of buprenorphine SL and placebo in patients with severe or very severe chronic cancer or noncancer pain. This multicenter, double-blind, placebo-controlled, parallel-group trial was 1 of 3 Phase III studies involved in the clinical development of buprenorphine TDS. It comprised a 6-day open-label run-in phase in which patients received buprenorphine SL 0.8 to 1.6 mg/d as needed and a double-blind phase in which patients were randomized to receive 3 sequential patches containing buprenorphine TES 35 microg/h or placebo, each lasting 72 hours. Rescue analgesia consisting of buprenorphine SL 02-mg tablets was available as needed throughout the double-blind phase. The main outcome measures were (1) the number of buprenorphine SL tablets required in addition to buprenorphine TES during the double-blind phase compared with the placebo group and compared with the buprenorphine SL requirement during the run-in phase, and (2) patients' assessments of pain intensity, pain relief, and duration of sleep uninterrupted by pain in the double-blind phase compared with the run-in phase. Adverse events were documented throughout the study. One hundred thirty-seven patients were included in the double-blind phase (90 buprenorphine TES, 47 placebo). The buprenorphine TES group included 47 men and 43 women (mean [SD] age, 56.0 [12.1] years), and the placebo group included 23 men and 24 women (mean age, 55.7 [12.9] years). Forty-five patients had cancer-related pain and 92 had noncancer-related pain. The 2 treatment groups were comparable with respect to sex distribution, age, height, and body weight Patients receiving buprenorphine TES significantly reduced their consumption of buprenorphine SL tablets in the double-blind phase compared with patients receiving placebo (reduction of 0.6 [0.4] mg vs 0.4 [0.4] mg; P = 0.03). The relationship between the buprenorphine SL dose in the run-in phase and the number of buprenorphine SL tablets required in the double-blind phase was dose dependent in the active-treatment group only. Patients' assessments of pain intensity and pain relief suggested better analgesia with buprenorphine TES than with placebo, although the differences did not reach statistical significance. The proportion of patients who reported sleeping for >6 hours uninterrupted by pain in the double-blind phase compared with the run-in phase increased by 6.4% in the buprenorphine TDS group (35.6% vs 292%, respectively), compared with a decrease of 5.9% in the placebo group (40.4% vs 463%); no statistical analysis of sleep duration data was performed. Buprenorphine TDS was well tolerated, with adverse events generally similar to those associated with other opioids. The incidence of systemic adverse events in the double-blind phase was similar in the 2 treatment groups (28.9% buprenorphine TDS, 27.6% placebo), with the most common adverse events being nausea, dizziness, and vomiting. After patch removal, skin reactions (mainly mild or moderate pruritus and erythema) were seen in 35.6% of the buprenorphine TDS group and 25.5% of the placebo group. In the population studied, buprenorphine TDS provided adequate pain relief, as well as improvements in pain intensity and duration of pain-free sleep. It may be considered a therapeutic option for the treatment of moderate to severe chronic pain.

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.

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.

Comparative evaluation of serum C-reactive protein levels in chronic and aggressive periodontitis patients and association with periodontal disease severity.

PubMed

Goyal, Lata; Bey, Afshan; Gupta, N D; Sharma, Vivek Kumar

2014-10-01

C-reactive protein (CRP) is an acute-phase reactant and has been proved to be a significant predictor of future cardiovascular events. Recent studies have demonstrated a correlation between periodontitis and elevated CRP levels. However, most of the studies have focused on chronic periodontitis and very few studies are done in patients with aggressive periodontitis. The aim of this study was to determine and compare the relative levels of serum CRP in aggressive and chronic periodontitis patients. A total of 75 systemically healthy subjects were divided into three groups: Group I, nonperiodontitis subjects; group II, chronic generalized periodontitis patients and group III, generalized aggressive periodontitis patients. All participants were subjected to quantitative CRP analysis using enzyme-linked immunosorbent assay. Mean CRP levels were significantly greater in both group II and III as compared to group I and group III having greater level than group II. Furthermore, CRP levels positively correlated with the amount of periodontal destruction as measured by probing depth and clinical attachment loss. The present study indicates a positive correlation between CRP and periodontal disease severity with particular concern in younger individuals that could be a possible underlying pathway in the association between periodontal disease and the observed higher risk for cardiovascular disease in periodontitis patients.

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.

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.

Dronedarone: current evidence and future questions.

PubMed

Schafer, Jeremy A; Kjesbo, Nicole K; Gleason, Patrick P

2010-01-01

Atrial fibrillation (AF) is the most common sustained arrhythmia, affecting more than 2.2 million Americans. ACC/AHA/ESC guidelines for the management of patients with AF recommend amiodarone for maintaining sinus rhythm. Dronedarone is a derivative of amiodarone indicated for the treatment of AF. To provide an overview of dronedarone with a focus on the phase III trials and discuss unresolved questions of dronedarone. A literature search was conducted via the PubMed database using the keyword "dronedarone." Search was limited to human trials in english. The FDA website was searched for briefing documents and subcommittee meetings on dronedarone. Clinicaltrials.gov was searched with the keyword dronedarone for upcoming or unpublished clinical trials. Five phase III trials are available for dronedarone: ANDROMEDA, EURIDIS/ADONIS, ATHENA, ERATO, and DIONYSIS. EURIDIS/ADONIS and ATHENA demonstrated a reduction AF recurrence with dronedarone compared to placebo. The ANDROMEDA trial recruited patients with recent hospitalization for heart failure and was terminated due to an excess of deaths in the dronedarone group. The DIONYSIS trial was a comparative effectiveness trial that demonstrated less efficacy for dronedarone but improved tolerability compared to amiodarone. Dronedarone represents an option in the management of AF in select patients. Dronedarone is not appropriate in patients with recently decompensated heart failure or those treated with strong CYP3A4 inhibitors or medications prolonging the QT interval. Dronedarone appears to have improved tolerability at the expense of decreased efficacy when compared to amiodarone. Questions remain on the long-term safety, use in patients with heart failure, retreatment after dronedarone or amiodarone failure, and comparative efficacy with a rate control strategy.

Scientometrics of drug discovery efforts: pain-related molecular targets.

PubMed

Kissin, Igor

2015-01-01

The aim of this study was to make a scientometric assessment of drug discovery efforts centered on pain-related molecular targets. The following scientometric indices were used: the popularity index, representing the share of articles (or patents) on a specific topic among all articles (or patents) on pain over the same 5-year period; the index of change, representing the change in the number of articles (or patents) on a topic from one 5-year period to the next; the index of expectations, representing the ratio of the number of all types of articles on a topic in the top 20 journals relative to the number of articles in all (>5,000) biomedical journals covered by PubMed over a 5-year period; the total number of articles representing Phase I-III trials of investigational drugs over a 5-year period; and the trial balance index, a ratio of Phase I-II publications to Phase III publications. Articles (PubMed database) and patents (US Patent and Trademark Office database) on 17 topics related to pain mechanisms were assessed during six 5-year periods from 1984 to 2013. During the most recent 5-year period (2009-2013), seven of 17 topics have demonstrated high research activity (purinergic receptors, serotonin, transient receptor potential channels, cytokines, gamma aminobutyric acid, glutamate, and protein kinases). However, even with these seven topics, the index of expectations decreased or did not change compared with the 2004-2008 period. In addition, publications representing Phase I-III trials of investigational drugs (2009-2013) did not indicate great enthusiasm on the part of the pharmaceutical industry regarding drugs specifically designed for treatment of pain. A promising development related to the new tool of molecular targeting, ie, monoclonal antibodies, for pain treatment has not yet resulted in real success. This approach has not yet demonstrated clinical effectiveness (at least with nerve growth factor) much beyond conventional analgesics, when its potential cost is more than an order of magnitude higher than that of conventional treatments. This scientometric assessment demonstrated a lack of real breakthrough developments.

The STAR trial protocol: a randomised multi-stage phase II/III study of Sunitinib comparing temporary cessation with allowing continuation, at the time of maximal radiological response, in the first-line treatment of locally advanced/metastatic Renal Cancer

PubMed Central

2012-01-01

Background Over recent years a number of novel therapies have shown promise in advanced renal cell carcinoma (RCC). Internationally the standard of care of first-line therapy is sunitinib™, after a clear survival benefit was demonstrated over interferon-α. Convention dictates that sunitinib is continued until evidence of disease progression, assuming tolerability, although there is no evidence that this approach is superior to intermittent periods of treatment. The purpose of the STAR trial is to compare the standard treatment strategy (conventional continuation strategy, CCS) with a novel drug free interval strategy (DFIS) which includes planned treatment breaks. Methods/Design The STAR trial is an NIHR HTA-funded UK pragmatic randomised phase II/III clinical trial in the first-line treatment of advanced RCC. Participants will be randomised (1:1) to either a sunitinib CCS or a DFIS. The overall aim of the trial is to determine whether a DFIS is non-inferior, in terms of 2-year overall survival (OS) and quality adjusted life years (QALY) (averaged over treatment and follow up), compared to a CCS. The QALY primary endpoint was selected to assess whether any detriment in terms of OS could be balanced with improvements in quality of life (QoL). This is a complex trial with a number of design challenges, and to address these issues a feasibility stage is incorporated into the trial design. Predetermined recruitment (stage A) and efficacy (stage B) intermediary endpoints must be met to allow continuation to the overall phase III trial (stage C). An integral qualitative patient preference and understanding study will occur alongside the feasibility stage to investigate patients’ feelings regarding participation or non-participation in the trial. Discussion The optimal duration of continuing sunitinib in advanced RCC is unknown. Novel targeted therapies do not always have the same constraints to treatment duration as standard chemotherapeutic agents and currently there are no randomised data comparing different treatment durations. Incorporating planned treatment breaks has the potential to improve QoL and cost effectiveness, hopefully without significant detriment on OS, as has been demonstrated in other cancer types with other treatments. Trial Registration Controlled-trials.com ISRCTN 06473203 PMID:23241439

Long-term effectiveness of ranibizumab for age-related macular degeneration and diabetic macular edema

PubMed Central

Fong, Angie HC; Lai, Timothy YY

2013-01-01

Neovascular age-related macular degeneration (AMD) and diabetic macular edema (DME) are major causes of visual impairment in the elderly population worldwide. With the aging population, the prevalence of neovascular AMD and DME has increased substantially over the recent years. Vascular endothelial growth factor (VEGF) has been implicated as playing an important role in the pathogenesis of both neovascular AMD and DME. Since its introduction in 2006, ranibizumab, a recombinant, humanized, monoclonal antibody fragment against all isoforms of VEGF-A, has revolutionized the treatment of neovascular AMD and DME. The efficacy and safety of ranibizumab in neovascular AMD has been demonstrated in the ANCHOR and MARINA trials. Further studies including the PIER, PrONTO, and SUSTAIN trials have also evaluated the optimal dosing regimen of ranibizumab in neovascular AMD. The CATT and IVAN trials compared the safety and efficacy of ranibizumab with off-label use of bevacizumab. Studies such as SUSTAIN and HORIZON have shown that ranibizumab has a good safety profile and is well tolerated for over 4 years with very few serious ocular and systemic adverse events. For DME, Phase II RESOLVE study and Phase III RISE and RIDE studies have demonstrated superiority of ranibizumab treatment in improving vision over placebo controls. Phase II READ and Phase III RESOLVE and REVEAL studies have shown that ranibizumab is more effective both as monotherapy and in combination with laser compared with laser monotherapy. The 3-year results from the DRCRnet protocol I study found that ranibizumab with deferred laser resulted in better long-term visual outcome compared with ranibizumab with prompt laser. This review summarizes various important clinical trials on the long-term efficacy and safety of ranibizumab in the treatment of neovascular AMD and DME. The pharmacological properties of ranibizumab, its cost effectiveness, and impact on quality of life will also be discussed. PMID:23766636

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.

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

PubMed

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

2014-03-01

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

TRIBE-2: a phase III, randomized, open-label, strategy trial in unresectable metastatic colorectal cancer patients by the GONO group.

PubMed

Cremolini, Chiara; Marmorino, Federica; Loupakis, Fotios; Masi, Gianluca; Antoniotti, Carlotta; Salvatore, Lisa; Schirripa, Marta; Boni, Luca; Zagonel, Vittorina; Lonardi, Sara; Aprile, Giuseppe; Tamburini, Emiliano; Ricci, Vincenzo; Ronzoni, Monica; Pietrantonio, Filippo; Valsuani, Chiara; Tomasello, Gianluca; Passardi, Alessandro; Allegrini, Giacomo; Di Donato, Samantha; Santini, Daniele; Falcone, Alfredo

2017-06-09

Chemotherapy plus bevacizumab is a standard first-line treatment for unresectable metastatic colorectal cancer patients. Different chemotherapy backbones may be chosen, including one to three drugs, based on patients' general conditions and comorbidities, treatments' objectives, and disease characteristics. TRIBE trial demonstrated a significant advantage in terms of progression-free survival and overall survival for FOLFOXIRI plus bevacizumab as compared with FOLFIRI plus bevacizumab. Based on recent evidence, the de-intensification of the upfront regimen after 4-6 months of treatment is nowadays regarded as a valuable option. Moreover, the prolonged inhibition of angiogenesis, and in particular the continuation of bevacizumab beyond the evidence of disease progression, is an efficacious strategy in the treatment of metastatic colorectal cancer patients. TRIBE-2 is a prospective, open-label, multicentric phase III randomized trial in which unresectable and previously untreated metastatic colorectal cancer patients are randomized to receive first-line FOLFOX plus bevacizumab followed by FOLFIRI plus bevacizumab after disease progression or FOLFOXIRI plus bevacizumab followed by the re-introduction of the same regimen after disease progression. The primary endpoint is to compare the efficacy of the two proposed treatment strategies in terms of Progression Free Survival 2. The TRIBE-2 study aims at answering the question whether the upfront use of FOLFOXIRI improves the clinical outcome of metastatic colorectal cancer patients, when compared with the pre-planned, sequential use of oxaliplatin-based and irinotecan-based doublets. Both proposed treatment strategies are designed to exploit the effectiveness of the prolonged inhibition of angiogenesis, alternating short (up to 4 months) induction periods and less intensive maintenance phases. TRIBE2 is registered at Clinicaltrials.gov: NCT02339116 . January 12, 2015. TRIBE-2 is registered at EUDRACT 2014-004436-19, October 10, 2014.

HSD3B2, HSD17B1, HSD17B2, ESR1, ESR2 and AR expression in infertile women with endometriosis.

PubMed

Osiński, Maciej; Wirstlein, Przemysław; Wender-Ożegowska, Ewa; Mikołajczyk, Mateusz; Jagodziński, Paweł Piotr; Szczepańska, Małgorzata

2018-01-01

The development of endometriosis is associated with changes in the expression of genes encoding the 3β-hydroxysteroid dehydrogenase type II (HSD3B2) and 17β-hydroxysteroid dehydrogenase type II (HSD17B2), estrogen receptors 1 (ESR1) and 2 (ESR2) and the androgen receptor (AR). However, little is known about the expression of HSD3B2, HSD17B1, HSD17B2, ESR1 ESR2 and AR during the endometrial phases in eutopic endometrium from infertile women with endometriosis. Using RT-qPCR analysis, we assessed the expression of the studied genes in the follicular and luteal phases in eutopic endometrium from fertile women (n = 17) and infertile women (n = 35) with endometriosis. In the mid-follicular eutopic endometrium, we observed a significant increase in HSD3B2 transcript levels in all infertile women with endometriosis (p = 0.003), in infertile women with stage I/II endometriosis (p = 0.008) and in infertile women with stage III/IV endometriosis (p = 0.009) compared to all fertile women. There was a significant increase in ESR1 tran-scripts in all infertile women with endometriosis (p = 0.008) and in infertile women with stage I/II endometriosis (p = 0.019) and in infertile women with stage III/IV endometriosis (p = 0.023) compared to all fertile women. In the mid-luteal eutopic endometrium, we did not observe significant differences in HSD3B2, HSD17B1, HSD17B2, ESR1, ESR2 and AR transcripts between infertile women with endometriosis and fertile women. Observed significant increase in HSD3B2 and ESR1 transcripts in follicular eutopic endometrium from infer-tile women with endometriosis may be related to abnormal biological effect of E2 in endometrium, further affecting the development of human embryos.

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.

Designing "Real-World" trials to meet the needs of health policy makers at marketing authorization.

PubMed

Calvert, Melanie; Wood, John; Freemantle, Nick

2011-07-01

There is increasing interest in conducting "Real-World" trials that go beyond traditional assessment of efficacy and safety to examine market access and value for money questions before marketing authorization of a new pharmaceutical product or health technology. This commentary uses practical examples to demonstrate how high-quality evidence of the cost-effectiveness of an intervention may be gained earlier in the development process. Issues surrounding the design and analysis of "Real-World" trials to demonstrate relative cost-effectiveness early in the life of new technologies are discussed. The modification of traditional phase III trial designs, de novo trial designs, the combination of trial-based and epidemiological data, and the use of simulation model-based approaches to address reimbursement questions are described. Modest changes to a phase III trial protocol and case report form may be undertaken at the design stage to provide valid estimates of health care use and the benefits accrued; however, phase III designs often preclude "real-life" practice. Relatively small de novo trials may be used to address adherence to therapy or patient preference, although simply designed studies with active comparators enrolling large numbers of patients may provide evidence on long-term safety and rare adverse events. Practical examples demonstrate that it is possible to provide high-quality evidence of the cost-effectiveness of an intervention earlier in the development process. Payers and decision makers should preferentially adopt treatments with such evidence than treatments for which evidence is lacking or of lower quality. Copyright © 2011 Elsevier Inc. All rights reserved.

Biotechnology stock prices before public announcements: evidence of insider trading?

PubMed

Overgaard, C B; van den Broek, R A; Kim, J H; Detsky, A S

2000-03-01

Unique financial challenges faced by biotechnology companies developing therapeutics have contributed to the creation of a highly sensitive market, where stock prices are capable of great fluctuation. The potential for significant financial reward and the nature of the scientific review process make this industry susceptible to illegal share trading on nonpublic information. We examined stock prices of biotechnology products before and after announcement of Phase III clinical trial and Food and Drug Administration (FDA) Advisory Panel results for indirect evidence of insider trading. Biotechnology stock prices were recorded for 98 products undergoing Phase III clinical trials and 49 products undergoing FDA Advisory Panel review between 1990 and 1998. Prices were recorded for 120 consecutive trading days before and after public announcement of these two events. We compared the average change in stock price of successful products ('winners') with unsuccessful products ('losers') before the public announcement of results for both critical events. The difference between average stock price change from 120 to 3 days before public announcement of results of Phase III clinical trial winners (+27%) and losers (-4%) was highly significant (P = 0.0007). A similar but non-significant difference was observed between the average stock price of winning (+27%) and losing products (+13%) before FDA Advisory Panel review announcements (P = 0.25). Our results provide indirect evidence that insider trading may be common in the biotechnology industry. Clinical investigators may wish to consider this issue before participating in any equity position in the biotechnology industry, especially if they are going to perform research for those companies.

Engineering HSV-1 vectors for gene therapy.

PubMed

Goins, William F; Huang, Shaohua; Cohen, Justus B; Glorioso, Joseph C

2014-01-01

Virus vectors have been employed as gene transfer vehicles for various preclinical and clinical gene therapy applications, and with the approval of Glybera (alipogene tiparvovec) as the first gene therapy product as a standard medical treatment (Yla-Herttuala, Mol Ther 20: 1831-1832, 2013), gene therapy has reached the status of being a part of standard patient care. Replication-competent herpes simplex virus (HSV) vectors that replicate specifically in actively dividing tumor cells have been used in Phase I-III human trials in patients with glioblastoma multiforme, a fatal form of brain cancer, and in malignant melanoma. In fact, T-VEC (talimogene laherparepvec, formerly known as OncoVex GM-CSF) displayed efficacy in a recent Phase III trial when compared to standard GM-CSF treatment alone (Andtbacka et al. J Clin Oncol 31: sLBA9008, 2013) and may soon become the second FDA-approved gene therapy product used in standard patient care. In addition to the replication-competent oncolytic HSV vectors like T-VEC, replication-defective HSV vectors have been employed in Phase I-II human trials and have been explored as delivery vehicles for disorders such as pain, neuropathy, and other neurodegenerative conditions. Research during the last decade on the development of HSV vectors has resulted in the engineering of recombinant vectors that are totally replication defective, nontoxic, and capable of long-term transgene expression in neurons. This chapter describes methods for the construction of recombinant genomic HSV vectors based on the HSV-1 replication-defective vector backbones, steps in their purification, and their small-scale production for use in cell culture experiments as well as preclinical animal studies.

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.

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.

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.

Nanoscale multiphase phase field approach for stress- and temperature-induced martensitic phase transformations with interfacial stresses at finite strains

NASA Astrophysics Data System (ADS)

Basak, Anup; Levitas, Valery I.

2018-04-01

A thermodynamically consistent, novel multiphase phase field approach for stress- and temperature-induced martensitic phase transformations at finite strains and with interfacial stresses has been developed. The model considers a single order parameter to describe the austenite↔martensitic transformations, and another N order parameters describing N variants and constrained to a plane in an N-dimensional order parameter space. In the free energy model coexistence of three or more phases at a single material point (multiphase junction), and deviation of each variant-variant transformation path from a straight line have been penalized. Some shortcomings of the existing models are resolved. Three different kinematic models (KMs) for the transformation deformation gradient tensors are assumed: (i) In KM-I the transformation deformation gradient tensor is a linear function of the Bain tensors for the variants. (ii) In KM-II the natural logarithms of the transformation deformation gradient is taken as a linear combination of the natural logarithm of the Bain tensors multiplied with the interpolation functions. (iii) In KM-III it is derived using the twinning equation from the crystallographic theory. The instability criteria for all the phase transformations have been derived for all the kinematic models, and their comparative study is presented. A large strain finite element procedure has been developed and used for studying the evolution of some complex microstructures in nanoscale samples under various loading conditions. Also, the stresses within variant-variant boundaries, the sample size effect, effect of penalizing the triple junctions, and twinned microstructures have been studied. The present approach can be extended for studying grain growth, solidifications, para↔ferro electric transformations, and diffusive phase transformations.

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.

Activity of Lower Limb Muscles During Squat With and Without Abdominal Drawing-in and Pilates Breathing.

PubMed

Barbosa, Alexandre C; Martins, Fábio M; Silva, Angélica F; Coelho, Ana C; Intelangelo, Leonardo; Vieira, Edgar R

2017-11-01

Barbosa, AC, Martins, FM, Silva, AF, Coelho, AC, Intelangelo, L, and Vieira, ER. Activity of lower limb muscles during squat with and without abdominal drawing-in and Pilates breathing. J Strength Cond Res 31(11): 3018-3023, 2017-The purpose of this study was to assess the effects of abdominal drawing-in and Pilates breathing on the activity of lower limb muscles during squats. Adults (n = 13, 22 ± 3 years old) with some Pilates experience performed three 60° squats under each of the following conditions in a random order: (I) normal breathing, (II) drawing-in maneuver with normal breathing, and (III) drawing-in maneuver with Pilates breathing. Peak-normalized surface electromyography of the rectus femoris, biceps femoris, gastrocnemius medialis, and tibialis anterior during the knee flexion and extension phases of squat exercises was analyzed. There were significant differences among the conditions during the knee flexion phase for the rectus femoris (p = 0.001), biceps femoris (p = 0.038), and tibialis anterior (p = 0.001), with increasing activation from conditions I to III. For the gastrocnemius medialis, there were significant differences among the conditions during the knee extension phase (p = 0.023), with increased activity under condition I. The rectus and biceps femoris activity was higher during the extension vs. flexion phase under conditions I and II. The tibialis anterior activity was higher during the flexion compared with the extension phase under all conditions, and the medial gastrocnemius activity was higher during the extension phase under condition I. Doing squats with abdominal drawing-in and Pilates breathing resulted in increased rectus, biceps femoris, and tibialis anterior activity during the flexion phase, increasing movement stability during squat exercises.

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

Treatment outcome of anti-angiogenesis through VEGF-pathway in the management of gastric cancer: a systematic review of phase II and III clinical trials.

PubMed

Mawalla, Brian; Yuan, Xianglin; Luo, Xiaoxiao; Chalya, Phillip L

2018-01-12

Advanced gastric cancer poses a therapeutic challenge worldwide. In randomised clinical trials, anti-VEGF has been reported as an essential agent for the treatment of advanced gastric cancer. This review aims at assessing the treatment outcome of anti-angiogenesis therapy through the VEGF pathway in the management of patients with advanced gastric cancer. During this review, 38 clinical trials were identified. Of these, 30 clinical trials were excluded, leaving eight trials of phase II and III. Ramucirumab, as a second line treatment of advanced gastric cancer, decreases the risk of disease progression (37-52%) and death (19-22%). Compare ramucirumab and bevacizumab in combination with traditional chemotherapy; ramucirumab has shown to improve progression-free survival and overall survival. Apatinib tyrosine kinase inhibitor combined with traditional chemotherapy has shown to improve overall response rate and progression-free survival with marginal improvements in overall survival. Chemotherapy, in combination with anti-VEGF drugs, in the management of advanced gastric cancer significantly improves the outcome of overall response rate, progression-free survival and overall survival when compared to chemotherapy alone. Therefore, we recommend that anti-VEGF drugs are the drugs of choice in the management of patients with advanced gastric cancer.

Class act: safety comparison of approved tyrosine kinase inhibitors for non-small-cell lung carcinoma.

PubMed

Burotto, Mauricio; Ali, Syed Abbas; O'Sullivan Coyne, Geraldine

2015-01-01

The past decade has seen the development and widespread use of tyrosine kinase inhibitors (TKIs) targeting a mutated EGFR (mEGFR) for the treatment of metastatic NSCLC. We discuss the main properties of the TKIs currently recommended for the treatment of mEGFR NSCLC: gefitinib, erlotinib and afatinib. The mechanism of action, pharmacodynamics and pharmacokinetics of these drugs, with emphasis on the historical context of their preclinical and clinical development, will be covered, including potential resistance mechanisms to these first-generation TKIs that has driven the trial design for second and third generations of EGFR inhibitors. Six Phase III clinical trials comparing these three TKIs with cisplatin-based chemotherapy upfront for mEGFR NSCLC provide the basis for the comparative safety and toxicity analysis between these agents. Class-related toxicity of these EGFR inhibitors, including life-threatening effects, will be discussed. Toxicity and safety analysis from the Phase III trials of these agents in mEGFR populations suggests that afatinib has more frequent and severe side effects. Given that an efficacy advantage has not yet been demonstrated for afatinib over erlotinib and gefitinib, the consistent class toxicity profile of these agents means that gefitinib and erlotinib are a safer first-line treatment recommendation.

Economics of recombinant antibody production processes at various scales: Industry-standard compared to continuous precipitation.

PubMed

Hammerschmidt, Nikolaus; Tscheliessnig, Anne; Sommer, Ralf; Helk, Bernhard; Jungbauer, Alois

2014-06-01

Standard industry processes for recombinant antibody production employ protein A affinity chromatography in combination with other chromatography steps and ultra-/diafiltration. This study compares a generic antibody production process with a recently developed purification process based on a series of selective precipitation steps. The new process makes two of the usual three chromatographic steps obsolete and can be performed in a continuous fashion. Cost of Goods (CoGs) analyses were done for: (i) a generic chromatography-based antibody standard purification; (ii) the continuous precipitation-based purification process coupled to a continuous perfusion production system; and (iii) a hybrid process, coupling the continuous purification process to an upstream batch process. The results of this economic analysis show that the precipitation-based process offers cost reductions at all stages of the life cycle of a therapeutic antibody, (i.e. clinical phase I, II and III, as well as full commercial production). The savings in clinical phase production are largely attributed to the fact that expensive chromatographic resins are omitted. These economic analyses will help to determine the strategies that are best suited for small-scale production in parallel fashion, which is of importance for antibody production in non-privileged countries and for personalized medicine. Copyright © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Robot-assisted laparoscopic gastrectomy for gastric cancer

PubMed Central

Caruso, Stefano; Franceschini, Franco; Patriti, Alberto; Roviello, Franco; Annecchiarico, Mario; Ceccarelli, Graziano; Coratti, Andrea

2017-01-01

Phase III evidence in the shape of a series of randomized controlled trials and meta-analyses has shown that laparoscopic gastrectomy is safe and gives better short-term results with respect to the traditional open technique for early-stage gastric cancer. In fact, in the East laparoscopic gastrectomy has become routine for early-stage gastric cancer. In contrast, the treatment of advanced gastric cancer through a minimally invasive way is still a debated issue, mostly due to worries about its oncological efficacy and the difficulty of carrying out an extended lymphadenectomy and intestinal reconstruction after total gastrectomy laparoscopically. Over the last ten years the introduction of robotic surgery has implied overcoming some intrinsic drawbacks found to be present in the conventional laparoscopic procedure. Robot-assisted gastrectomy with D2 lymphadenectomy has been shown to be safe and feasible for the treatment of gastric cancer patients. But unfortunately, most available studies investigating the robotic gastrectomy for gastric cancer compared to laparoscopic and open technique are so far retrospective and there have not been phase III trials. In the present review we looked at scientific evidence available today regarding the new high-tech surgical robotic approach, and we attempted to bring to light the real advantages of robot-assisted gastrectomy compared to the traditional laparoscopic and open technique for the treatment of gastric cancer. PMID:28101302

Pressure effect on the long-range order in CeB6

NASA Astrophysics Data System (ADS)

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

2006-08-01

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

Preparation of III-V semiconductor nanocrystals

DOEpatents

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

1996-04-09

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

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

PubMed

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

2018-05-10

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

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).

Performance comparison of three types of high-speed counter-current chromatographs for the separation of components of hydrophilic and hydrophobic color additives.

PubMed

Weisz, Adrian; Ito, Yoichiro

2011-09-09

The performance of three types of high-speed counter-current chromatography (HSCCC) instruments was assessed for their use in separating components in hydrophilic and hydrophobic dye mixtures. The HSCCC instruments compared were: (i) a J-type coil planet centrifuge (CPC) system with a conventional multilayer-coil column, (ii) a J-type CPC system with a spiral-tube assembly-coil column, and (iii) a cross-axis CPC system with a multilayer-coil column. The hydrophilic dye mixture consisted of a sample of FD&C Blue No. 2 that contained mainly two isomeric components, 5,5'- and 5,7'-disulfonated indigo, in the ratio of ∼7:1. The hydrophobic dye mixture consisted of a sample of D&C Red No. 17 (mainly Sudan III) and Sudan II in the ratio of ∼4:1. The two-phase solvent systems used for these separations were 1-butanol/1.3M HCl and hexane/acetonitrile. Each of the three instruments was used in two experiments for the hydrophilic dye mixture and two for the hydrophobic dye mixture, for a total of 12 experiments. In one set of experiments, the lower phase was used as the mobile phase, and in the second set of experiments, the upper phase was used as the mobile phase. The results suggest that: (a) use of a J-type instrument with either a multilayer-coil column or a spiral-tube assembly column, applying the lower phase as the mobile phase, is preferable for separating the hydrophilic components of FD&C Blue No. 2; and (b) use of a J-type instrument with multilayer-coil column, while applying either the upper phase or the lower phase as the mobile phase, is preferable for separating the hydrophobic dye mixture of D&C Red No. 17 and Sudan II. Published by Elsevier B.V.

Exploring the high-pressure behavior of the three known polymorphs of BiPO{sub 4}: Discovery of a new polymorph

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

Errandonea, D., E-mail: daniel.errandonea@uv.es; García-Domene, B.; Gomis, O.

We have studied the structural behavior of bismuth phosphate under compression. We performed x-ray powder diffraction measurements up to 31.5 GPa and ab initio calculations. Experiments were carried out on different polymorphs: trigonal (phase I) and monoclinic (phases II and III). Phases I and III, at low pressure (P < 0.2–0.8 GPa), transform into phase II, which has a monazite-type structure. At room temperature, this polymorph is stable up to 31.5 GPa. Calculations support these findings and predict the occurrence of an additional transition from the monoclinic monazite-type to a tetragonal scheelite-type structure (phase IV). This transition was experimentally found after the simultaneous applicationmore » of pressure (28 GPa) and temperature (1500 K), suggesting that at room temperature the transition might by hindered by kinetic barriers. Calculations also predict an additional phase transition at 52 GPa, which exceeds the maximum pressure achieved in the experiments. This transition is from phase IV to an orthorhombic barite-type structure (phase V). We also studied the axial and bulk compressibility of BiPO{sub 4}. Room-temperature pressure-volume equations of state are reported. BiPO{sub 4} was found to be more compressible than isomorphic rare-earth phosphates. The discovered phase IV was determined to be the less compressible polymorph of BiPO{sub 4}. On the other hand, the theoretically predicted phase V has a bulk modulus comparable with that of monazite-type BiPO{sub 4}. Finally, the isothermal compressibility tensor for the monazite-type structure is reported at 2.4 GPa showing that the direction of maximum compressibility is in the (0 1 0) plane at approximately 15° (21°) to the a axis for the case of our experimental (theoretical) study.« 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

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.

Soluble Mesothelin Related Peptide (SMRP) and Osteopontin (OPN) as Early Detection Markers for Malignant Mesothelioma (MM) — EDRN Public Portal

Cancer.gov

Phase I: - Identification and assemblage of representative cohorts of individuals with MM, no malignancies but increased risk for MM due to asbestos exposure, and (optionally) lung malignancies other than MM Phase II (A) - Determine the sensitivity and specificity of SMRP and OPN in distinguishing individuals with a clinical diagnosis of malignant mesothelioma from individuals who are asbestos-exposed but without a clinical diagnosis of malignant mesothelioma. Phase II (B) – Determine the comparability of analyte values across contributing centers and determine covariates that influence analyte levels Phase II (C) – Determine the sensitivity and specificity of SMRP and OPN, alone and in combination, in distinguishing individuals with MM from those without. Phase III. Determine the sensitivity and specificity of SMRP and OPN in distinguishing individuals who would subsequently develop malignant mesothelioma from matched individuals who did not subsequently develop malignant mesothelioma. Phase IV. Determine the sensitivity and specificity of SMRP and OPN in other populations of interest.

Experiment evaluates ocean models and data assimiliation in the Gulf Stream

NASA Astrophysics Data System (ADS)

Willems, Robert C.; Glenn, S. M.; Crowley, M. F.; Malanotte-Rizzoli, P.; Young, R. E.; Ezer, T.; Mellor, G. L.; Arango, H. G.; Robinson, A. R.; Lai, C.-C. A.

Using data sets of known quality as the basis for comparison, a recent experiment explored the Gulf Stream Region at 27°-47°N and 80°-50°W to assess the nowcast/forecast capability of specific ocean models and the impact of data assimilation. Scientists from five universities and the Naval Research Laboratory/Stennis Space Center participated in the Data Assimilation and Model Evaluation Experiment (DAMEÉ-GSR).DAMEÉ-GSR was based on case studies, each successively more complex, and was divided into three phases using case studies (data) from 1987 and 1988. Phase I evaluated models' forecast capability using common initial conditions and comparing model forecast fields with observational data at forecast time over a 2-week period. Phase II added data assimilation and assessed its impact on forecast capability, using the same case studies as in phase I, and phase III added a 2-month case study overlapping some periods in Phases I and II.

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.

Connection between nitrogen and manganese cycles revealed by transcriptomic analysis in Shewanella algae C6G3

NASA Astrophysics Data System (ADS)

Michotey, V.; Aigle, A.; Armougom, F.; Mejean, V.; Guasco, S.; Bonin, P.

2016-02-01

In sedimentary systems, the repartition of terminal electron-accepting molecules is often stratified on a permanent or seasonal basis. Just below to oxic zone, the suboxic one is characterized by high concentrations of oxidized inorganic compounds such as nitrate, manganese oxides (MnIII/IV) and iron oxides that are in close vicinity. Several studies have reported unexpected anaerobic nitrite/nitrate production at the expense of ammonium mediated by MnIII/IV, however this transient processes is difficult to discern and poorly understood. In the frame of this study, genes organization of nitrate and MnIII/IV respiration was investigated in S.algae. Additional genes were identified in S. algae compare to S. oneidensis: genes coding for nitrate and nitrite reductase (napA-a and nrfA-2) and an OMC protein (mtrH). In contrast to S. oneidensis, an anaerobic transitory nitrite accumulation at the expense of ammonium was observed in S. algae during growth with MnIII/IV, concomitantly with expression of nitrate/nitrite reductase genes (napA, nrfA, nrfA-2). Among the hypothesis explaining this data, the potential putative expression of unidentified gene able to perform ammonium oxidation was not observed on the global transcriptional level, however several signs of oxidative stress were detected and the existence of a secondary reaction generated by a putative oxidative s could not be excluded. Another option could be the action of reverse reaction by an enzyme such as NrfA or NrfA-2 due to the electron flow equilibrium. Whatever the electron acceptor (Nitrate/ MnIII/IV), the unexpected expression level of of omcA, mtrF, mtrH, mtrC was observed and peaked at the end of the exponential phase. Different expression patterns of the omc genes were observed depending on electron acceptor and growth phase. Only mtrF-2 gene was specifically expressed in Mn(III/IV) condition. Nitrate and Mn(III/IV) respirations seem connected at physiological as well as at transcriptional level

Phase III, efficacy and safety study of ertugliflozin monotherapy in people with type 2 diabetes mellitus inadequately controlled with diet and exercise alone.

PubMed

Terra, Steven G; Focht, Kristen; Davies, Melanie; Frias, Juan; Derosa, Giuseppe; Darekar, Amanda; Golm, Gregory; Johnson, Jeremy; Saur, Didier; Lauring, Brett; Dagogo-Jack, Sam

2017-05-01

To conduct a phase III study to evaluate the efficacy and safety of ertugliflozin monotherapy in people with type 2 diabetes. This was a 52-week, double-blind, multicentre, randomized, parallel-group study with a 26-week, placebo-controlled treatment period (phase A), followed by a 26-week active-controlled treatment period (phase B) in 461 men and women, aged ≥18 years with inadequate glycaemic control (glycated haemoglobin [HbA1c] concentration 7.0% to 10.5% [53-91 mmol/mol], inclusive) despite diet and exercise. Results from phase A are reported in the present paper. The primary endpoint was the change in HbA1c from baseline to week 26. At week 26, the placebo-adjusted least squares mean HbA1c changes from baseline were -0.99% and -1.16% for the ertugliflozin 5 and 15 mg doses, respectively ( P  < .001 for both doses). The odds of having HbA1c <7.0% (53 mmol/mol) were significantly greater in the ertugliflozin 5 and 15 mg groups compared with the placebo group. Both doses of ertugliflozin significantly lowered fasting plasma glucose and 2-hour postprandial glucose levels and body weight. The placebo-adjusted differences in changes from baseline in systolic blood pressure were not statistically significant. A higher incidence of genital mycotic infections occurred in men and women treated with ertugliflozin compared with placebo. There was no significant difference between treatments in the proportion of participants with symptomatic hypoglycaemia or adverse events associated with urinary tract infection or hypovolaemia. Ertugliflozin 5 and 15 mg treatment for 26 weeks provides effective glycaemic control, reduces body weight and is generally well tolerated, when used as monotherapy. © 2017 John Wiley & Sons Ltd.

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

Prevention of Posttraumatic Contractures with Ketotifen (PERK)

DTIC Science & Technology

2017-10-01

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

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

ERIC Educational Resources Information Center

Marzano Research Laboratory, 2011

2011-01-01

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

Army Enlisted Personnel Competency Assessment Program: Phase III Pilot Tests

DTIC Science & Technology

2007-03-01

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

Rimonabant Sanofi-Synthélabo.

PubMed

Fernandez, Jose R; Allison, David B

2004-04-01

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

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

PubMed

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

2012-06-15

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

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.

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].

A Kinetic Model for GaAs Growth by Hydride Vapor Phase Epitaxy

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

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

2016-11-21

Precise control of the growth of III-V materials by hydride vapor phase epitaxy (HVPE) is complicated by the fact that the growth rate depends on the concentrations of nearly all inputs to the reactor and also the reaction temperature. This behavior is in contrast to metalorganic vapor phase epitaxy (MOVPE), which in common practice operates in a mass transport limited regime where growth rate and alloy composition are controlled almost exclusively by flow of the Group III precursor. In HVPE, the growth rate and alloy compositions are very sensitive to temperature and reactant concentrations, which are strong functions of themore » reactor geometry. HVPE growth, particularly the growth of large area materials and devices, will benefit from the development of a growth model that can eventually be coupled with a computational fluid dynamics (CFD) model of a specific reactor geometry. In this work, we develop a growth rate law using a Langmuir-Hinshelwood (L-H) analysis, fitting unknown parameters to growth rate data from the literature that captures the relevant kinetic and thermodynamic phenomena of the HVPE process. We compare the L-H rate law to growth rate data from our custom HVPE reactor, and develop quantitative insight into reactor performance, demonstrating the utility of the growth model.« less

The Use of Invisalign® System in the Management of the Orthodontic Treatment before and after Class III Surgical Approach

PubMed Central

2016-01-01

The approach to skeletal dysmorphisms in the maxillofacial area usually requires an orthodontic treatment by means of fixed appliances, both before and after the surgical phase. Since its introduction, Invisalign system has become a popular treatment choice for the clinicians because of the aesthetics and comfort of the removable clear aligners compared with the traditional appliances. Therefore, the aim of the present report was to illustrate the management of a malocclusion by means of Invisalign system associated with the traditional surgical technique. The present paper shows a case of a 23-year-old male patient characterized by a Class III malocclusion with lateral deviation of the mandible to the left side and cross-bite on teeth 2.2, 2.3, and 2.4. Invisalign system was used during the pre- and postsurgical phases rather than fixed appliances. The posttreatment cephalometric analysis emphasized the stability of the dental and skeletal symmetry corrections, occlusion and functional balance, over a 6-year follow-up. The results achieved at the end of the treatment showed how Invisalign can be effective in the management of the orthodontic phases in orthognathic surgery. The follow-up after 6 years emphasizes the stability of the treatment over time. PMID:27429811

Role of regorafenib as second-line therapy and landscape of investigational treatment options in advanced hepatocellular carcinoma

PubMed Central

Trojan, Jörg; Waidmann, Oliver

2016-01-01

Sorafenib is still the only systemic drug approved for the treatment of advanced hepatocellular carcinoma (HCC). In recent years, several investigational agents mainly targeting angiogenesis failed in late-phase clinical development due to either toxicity or lack of benefit. Recently, data of the RESORCE trial, a placebo-controlled Phase III study that evaluated the efficacy and safety of regorafenib in patients with HCC and documented disease progression after systemic first-line treatment with sorafenib, were presented at the ESMO World Congress on Gastrointestinal Cancer, 2016. Regorafenib treatment resulted in a 2.8-month survival benefit compared to placebo (10.6 months vs 7.8 months). Side effects were consistent with the known profile of regorafenib. The approval of regorafenib for this indication is expected in 2017. Further candidate agents in Phase III evaluation for second-line treatment of patients with HCC are the MET inhibitors tivantinib and cabozantinib, the vascular endothelial growth factor receptor-2 antibody ramucirumab, and the programmed death receptor-1 (PD-1) blocking antibody pembrolizumab. Furthermore, results from two first-line trials with either the tyrosine kinase inhibitor lenvatinib or the PD-1 antibody nivolumabin in comparison to sorafenib are awaited in the near future and might further change the treatment sequence of advanced HCC. PMID:27703962

Role of regorafenib as second-line therapy and landscape of investigational treatment options in advanced hepatocellular carcinoma.

PubMed

Trojan, Jörg; Waidmann, Oliver

2016-01-01

Sorafenib is still the only systemic drug approved for the treatment of advanced hepatocellular carcinoma (HCC). In recent years, several investigational agents mainly targeting angiogenesis failed in late-phase clinical development due to either toxicity or lack of benefit. Recently, data of the RESORCE trial, a placebo-controlled Phase III study that evaluated the efficacy and safety of regorafenib in patients with HCC and documented disease progression after systemic first-line treatment with sorafenib, were presented at the ESMO World Congress on Gastrointestinal Cancer, 2016. Regorafenib treatment resulted in a 2.8-month survival benefit compared to placebo (10.6 months vs 7.8 months). Side effects were consistent with the known profile of regorafenib. The approval of regorafenib for this indication is expected in 2017. Further candidate agents in Phase III evaluation for second-line treatment of patients with HCC are the MET inhibitors tivantinib and cabozantinib, the vascular endothelial growth factor receptor-2 antibody ramucirumab, and the programmed death receptor-1 (PD-1) blocking antibody pembrolizumab. Furthermore, results from two first-line trials with either the tyrosine kinase inhibitor lenvatinib or the PD-1 antibody nivolumabin in comparison to sorafenib are awaited in the near future and might further change the treatment sequence of advanced HCC.

Influence of Magnetite Stoichiometry on the Binding of Emerging Organic Contaminants.

PubMed

Cheng, Wei; Marsac, Rémi; Hanna, Khalil

2018-01-16

While the magnetite stoichiometry (i.e., Fe(II)/Fe(III) ratio) has been extensively studied for the reductive transformation of chlorinated or nitroaromatic compounds, no work exists examining the influence of stoichiometry of magnetite on its binding properties. This study, for the first time, demonstrates that the stoichiometry strongly affects the capacity of magnetite to bind not only quinolone antibiotics such as nalidixic acid (NA) and flumequine (FLU), but also salicylic acid (SA), natural organic matter (humic acid, HA), and dissolved silicates. Fe(II)-amendment of nonstoichiometric magnetite (Fe(II)/Fe(III) = 0.40) led to similar sorbed amounts of NA, FLU, SA, silicates or HA as compared to the stoichiometric magnetite (i.e., Fe(II)/Fe(III) = 0.50). At any pH between 6 and 10, all magnetites exhibiting similar Fe(II)/Fe(III) ratio in the solid phase showed similar adsorption properties for NA or FLU. This enhancement in binding capability of magnetite for NA is still observed in the presence of environmentally relevant ligands (e.g., 10 mg L -1 of HA or 100 μM of silicates). Using surface complexation modeling, it was shown that the NA-magnetite complexation constant does not vary with Fe(II)/Fe(III) between 0.24 and 0.40, but increases by 8 orders of magnitude when Fe(II)/Fe(III) increases from 0.40 to 0.50.

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.

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.

First principles study of pressure induced polymorphic phase transition in KNO3

NASA Astrophysics Data System (ADS)

Yedukondalu, N.; Vaitheeswaran, G.

2015-06-01

We report the structural, elastic, electronic, and vibrational properties of polymorphic phases II and III of KNO3 based on density functional theory (DFT). Using semi-empirical dispersion correction (DFT-D2) method, we predicted the correct thermodynamic ground state of KNO3 and the obtained ground state properties of the polymorphs are in good agreement with the experiments. We further used this method to calculate the elastic constants, IR and Raman spectra, vibrational frequencies and their assignment of these polymorphs. The calculated Tran Blaha-modified Becke Johnson (TB-mBJ) electronic structure shows that both the polymorphic phases are direct band gap insulators with mixed ionic and covalent bonding. Also the TB-mBJ band gaps are improved over standard DFT functionals which are comparable with the available experiments.

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.

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.

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

PubMed Central

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

2017-01-01

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

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.

Does Concurrent Radiochemotherapy Affect Cosmetic Results in the Adjuvant Setting After Breast-Conserving Surgery? Results of the ARCOSEIN Multicenter, Phase III Study: Patients' and Doctors' Views

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

Toledano, Alain H.; Bollet, Marc A.; Fourquet, Alain

2007-05-01

Purpose: To evaluate the cosmetic results of sequential vs. concurrent adjuvant chemotherapy with radiotherapy after breast-conserving surgery for breast cancer, and to compare ratings by patients and physicians. Methods and Materials: From 1996 to 2000, 716 patients with Stage I-II breast cancers were included in a multicenter, Phase III trial (the ARCOSEIN study) comparing, after breast-conserving surgery with axillary dissection, sequential treatment with chemotherapy first followed by radiotherapy vs. chemotherapy administered concurrently with radiotherapy. Cosmetic results with regard to both the overall aspect of the breast and specific changes (color, scar) were evaluated in a total of 214 patients (107more » in each arm) by means of questionnaires to both the patient and a physician whose rating was blinded to treatment allocation. Results: Patients' overall satisfaction with cosmesis was not statistically different between the two arms, with approximately 92% with at least satisfactory results (p = 0.72), although differences between the treated and untreated breasts were greater after the concurrent regimen (29% vs. 14% with more than moderate differences; p 0.0015). Physician assessment of overall cosmesis was less favorable, with lower rates of at least satisfactory results in the concurrent arm (60% vs. 85%; p = 0.001). Consequently, the concordance for overall satisfaction with cosmesis between patients and doctors was only fair ({kappa} = 0.62). Conclusion: After breast-conserving surgery, the concurrent use of chemotherapy with radiotherapy is significantly associated with greater differences between the breasts. These differences do not translate into patients' lessened satisfaction with cosmesis.« less

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.

Influence of motivating operations and discriminative stimuli on challenging behavior maintained by positive reinforcement.

PubMed

Edrisinha, Chaturi; O'Reilly, Mark; Sigafoos, Jeff; Lancioni, Giulio; Choi, Ha Young

2011-01-01

We examined the effects of an establishing operation (EO) and abolishing operation (AO) on stimulus control of challenging behavior. Two participants with developmental disabilities and challenging behavior participated. In Phase I, a functional analysis was conducted to identify the consequences maintaining challenging behavior. In Phase II, a discrimination between SD and SΔ was trained. In Phase III, pre-session MOs (i.e., EO and AO conditions) were arranged to assess their effects on challenging behavior. Finally in Phase IV, in addition to manipulating pre-session MOs the challenging behavior was evaluated under extinction in both SD and SΔ conditions. Results indicated that in the context of extinction when pre-session EO and AO conditions were manipulated, responding not only became differentiated but was higher in both SD and SΔ conditions in the pre-session EO condition when compared to the pre-session AO condition. Published by Elsevier Ltd.

Integrating Comparative Effectiveness Design Elements and Endpoints Into a Phase III, Randomized Clinical Trial (SWOG S1007) Evaluating OncotypeDX-Guided Management for Women With Breast Cancer Involving Lymph Nodes

PubMed Central

Ramsey, Scott D.; Barlow, William E.; Gonzalez-Angulo, Ana M.; Tunis, Sean; Baker, Laurence; Crowley, John; Deverka, Patricia; Veenstra, David; Hortobagyi, Gabriel N.

2012-01-01

Women with breast cancer involving the lymph nodes are typically treated with cytotoxic chemotherapy. Retrospective evaluations of prior studies suggest that the 21-gene test (OncotypeDX®), may allow identification of those who can safely avoid chemotherapy. To better understand the performance of the 21-gene test, the RxPONDER (Rx for Positive Node, Endocrine Responsive breast cancer) study was designed, a multicenter Phase III trial randomizing women with hormone receptor-positive and HER2-negative breast cancer involving 1–3 lymph nodes and a 21-gene assay recurrence score (RS) of 25 or less to endocrine therapy alone versus chemotherapy followed by endocrine therapy. As one of the first large-scale comparative-effectiveness studies in oncology, RxPONDER utilized an external stakeholder group to help inform the design of the trial. Stakeholders met with representatives of SWOG over several months through a structured discussion process. The stakeholder engagement process resulted in several changes being made to the trial design. In addition, stakeholder representatives from the health insurance industry provided guidance regarding a mechanism whereby the costs of OncotypeDX® would be paid by the majority of health insurers as part of the trial. The process may serve as a template for future studies evaluating the comparative effectiveness of genomic tests in oncology, particularly those that are conducted within cooperative clinical trials groups. PMID:23000081

Lanreotide autogel every 6 weeks compared with Lanreotide microparticles every 3 weeks in patients with well differentiated neuroendocrine tumors: a Phase III Study.

PubMed

Bajetta, Emilio; Procopio, Giuseppe; Catena, Laura; Martinetti, Antonia; De Dosso, Sara; Ricci, Sergio; Lecchi, Alberto S; Boscani, Paolo F; Iacobelli, Stefano; Carteni, Giacomo; De Braud, Filippo; Loli, Paola; Tartaglia, Andreas; Bajetta, Roberto; Ferrari, Leonardo

2006-11-15

The noninferiority of a 6-week dosing schedule of lanreotide Autogel (Lan ATG) at a dose of 120 mg compared with a 3-week dosing schedule of lanreotide microparticles (Lan MP) at a dose of 60 mg was investigated in patients with neuroendocrine tumors (NET). Patients who had sporadic, well differentiated NET with a low grade of malignancy were recruited for this open-label, Phase III, multicenter trial. Patients were randomized to receive either 3 deep subcutaneous injections of Lan ATG (120 mg, every 6 weeks) or 6 intramuscular injections of Lan MP (60 mg, every 3 weeks). Tumor markers, tumor size, and symptoms were assessed between baseline and Week 18. Success was classified as a response that ranged from disappearance to an increase <25% in tumor marker, tumor size, or symptom frequency. Sixty patients were randomized, and 46 patients completed the study. Both for tumor markers and for tumor size, Lan ATG was not inferior to Lan MP (55% and 59% of patients responded on tumor markers, respectively; 68% and 66% of patients responded on tumor size, respectively). There were too few symptomatic patients to compare carcinoid symptoms. Both treatments were tolerated well, and no safety concerns were identified. Lan ATG at a dose of 120 mg every 6 weeks was as effective for controlling NET as Lan MP at a dose of 60 mg every 3 weeks.

Arsenite and Ferrous Iron Oxidation Linked to Chemolithotrophic Denitrification for the Immobilization of Arsenic in Anoxic Environments

PubMed Central

Sun, Wenjie; Sierra-Alvarez, Reyes; Milner, Lily; Oremland, Ron; Field, Jim A.

2014-01-01

The objective of this study was to explore a bioremediation strategy based on injecting NO3− to support the anoxic oxidation of ferrous iron (Fe(II)) and arsenite (As(III)) in the subsurface as a means to immobilize As in the form of arsenate (As(V)) adsorbed onto biogenic ferric (Fe(III)) (hydr)oxides. Continuous flow sand filled columns were used to simulate a natural anaerobic groundwater and sediment system with co-occurring As(III) and Fe(II) in the presence (SF1) or absence (SF2) of nitrate, respectively. During operation for 250 days, the average influent arsenic concentration of 567 µg l−1 was reduced to 10.6 (±9.6) µg l−1 in the effluent of column SF1. The cumulative removal of Fe(II) and As(III) in SF1 was 6.5–10-fold higher than that in SF2. Extraction and measurement of the mass of iron and arsenic immobilized on the sand packing of the columns was close to the iron and arsenic removed from the aqueous phase during column operation. The dominant speciation of the immobilized iron and arsenic was Fe(III) and As(V) in SF1, compared with Fe(II) and As(III) in SF2. The speciation was confirmed by XRD and XPS. The results indicate that microbial oxidation of As(III) and Fe(II) linked to denitrification resulted in the enhanced immobilization of aqueous arsenic in anaerobic environments by forming Fe(III) (hydr)oxides coated sands with adsorbed As(V). PMID:19764221

Polymethacrylate Polymers with Appended Aluminum(III)-Tetraphenylporphyrins: Synthesis, Characterization and Evaluation as Macromolecular Ionophores for Electrochemical and Optical Fluoride Sensors

PubMed Central

Wang, Lin; Meyerhoff, Mark E.

2008-01-01

The synthesis and characterization of a novel polymethacylate polymer with covalently linked Al(III)-tetraphenylporphyrin (Al(III)-TPP) groups is reported. The new polymer is examined as a potential macromolecular ionophore for the preparation of polymeric membrane-based potentiometric and optical fluoride selective sensors. To prepare the polymer, an Al(III) porphyrin monomer modified with a methacrylate functionality is synthesized, allowing insertion into a polymethacrylate block copolymer (methyl methacrylate and decyl methacrylate) backbone. The resulting polymer can then be incorporated, along with appropriate additives, into conventional plasticized poly(vinyl chloride) films for testing electrochemical and optical fluoride response properties. The covalent attachment of the Al(III)-TPP ionophore to the copolymer matrix provides potentiometric sensors that exhibit significant selectivity for fluoride ion with extended lifetimes (compared to ion-selective membrane electrodes formulated with conventional free Al(III)-TPP structure). However, quite surprisingly, the attachment of the ionophore to the polymer does not eliminate the interaction of Al(III)-TPP structures to form dimeric species within the membrane phase in the presence of fluoride ion. Such interactions are confirmed by UV/visible spectroscopy of the blended polymeric films. Use of the new polymer-Al(III)-TPP conjugates to prepare optical fluoride sensors by co-incorporating a lipophilic pH indicator (4’,5’-dibromofluorescein octadecyl ester; ETH7075) is also examined and the resulting optical sensing films are shown to exhibit excellent selectivity for fluoride, with the potential for prolonged operational lifetime. PMID:18298973

Ferric iron amendment increases Fe(III)-reducing microbial diversity and carbon oxidation in on-site wastewater systems.

PubMed

Azam, Hossain M; Finneran, Kevin T

2013-01-01

Onsite wastewater systems, or septic tanks, serve approximately 25% of the United States population; they are therefore a critical component of the total carbon balance for natural water bodies. Septic tanks operate under strictly anaerobic conditions, and fermentation is the dominant process driving carbon transformation. Nitrate, Fe(III), and sulfate reduction may be operating to a limited extent in any given septic tank. Electron acceptor amendments will increase carbon oxidation, but nitrate is toxic and sulfate generates corrosive sulfides, which may damage septic system infrastructure. Fe(III) reducing microorganisms transform all major classes of organic carbon that are dominant in septic wastewater: low molecular weight organic acids, carbohydrate monomers and polymers, and lipids. Fe(III) is not toxic, and the reduction product Fe(II) is minimally disruptive if the starting Fe(III) is added at 50-150 mg L(-1). We used (14)C radiolabeled acetate, lactate, propionate, butyrate, glucose, starch, and oleic acid to demonstrate that short and long-term carbon oxidation is increased when different forms of Fe(III) are amended to septic wastewater. The rates of carbon mineralization to (14)CO(2) increased 2-5 times (relative to unamended systems) in the presence of Fe(III). The extent of mineralization reached 90% for some carbon compounds when Fe(III) was present, compared to levels of 50-60% in the absence of Fe(III). (14)CH(4) was not generated when Fe(III) was added, demonstrating that this strategy can limit methane emissions from septic systems. Amplified 16S rDNA restriction analysis indicated that unique Fe(III)-reducing microbial communities increased significantly in Fe(III)-amended incubations, with Fe(III)-reducers becoming the dominant microbial community in several incubations. The form of Fe(III) added had a significant impact on the rate and extent of mineralization; ferrihydrite and lepidocrocite were favored as solid phase Fe(III) and chelated Fe(III) (with nitrilotriacetic acid or EDTA) as soluble Fe(III) forms. Copyright © 2012 Elsevier Ltd. All rights reserved.

Efficacy and safety of tolvaptan in heart failure patients with volume overload despite the standard treatment with conventional diuretics: a phase III, randomized, double-blind, placebo-controlled study (QUEST study).

PubMed

Matsuzaki, Masunori; Hori, Masatsugu; Izumi, Tohru; Fukunami, Masatake

2011-12-01

Diuretics are recommended to treat volume overload with heart failure (HF), however, they may cause serum electrolyte imbalance, limiting their use. Moreover, patients with advanced HF could poorly respond to these diuretics. In this study, we evaluated the efficacy and safety of Tolvaptan, a competitive vasopressin V2-receptor antagonist developed as a new drug to treat volume overload in HF patients. A phase III, multicenter, randomized, double-blind, placebo-controlled parallel study was performed to assess the efficacy and safety of tolvaptan in treating HF patients with volume overload despite the use of conventional diuretics. One hundred and ten patients were randomly assigned to receive either placebo or 15 mg/day tolvaptan for 7 consecutive days. Compared with placebo, tolvaptan administered for 7 days significantly reduced body weight and improved symptoms associated with volume overload. The safety profile of tolvaptan was considered acceptable for clinical use with minimal adverse effects. Tolvaptan reduced volume overload and improved congestive symptoms associated with HF by a potent water diuresis (aquaresis).

Construction of Polynuclear Lanthanide (Ln = Dy(III), Tb(III), and Nd(III)) Cage Complexes Using Pyridine-Pyrazole-Based Ligands: Versatile Molecular Topologies and SMM Behavior.

PubMed

Bala, Sukhen; Sen Bishwas, Mousumi; Pramanik, Bhaskar; Khanra, Sumit; Fromm, Katharina M; Poddar, Pankaj; Mondal, Raju

2015-09-08

Employment of two different pyridyl-pyrazolyl-based ligands afforded three octanuclear lanthanide(III) (Ln = Dy, Tb) cage compounds and one hexanuclear neodymium(III) coordination cage, exhibiting versatile molecular architectures including a butterfly core. Relatively less common semirigid pyridyl-pyrazolyl-based asymmetric ligand systems show an interesting trend of forming polynuclear lanthanide cage complexes with different coordination environments around the metal centers. It is noteworthy here that construction of lanthanide complex itself is a challenging task in a ligand system as soft N-donor rich as pyridyl-pyrazol. We report herein some lanthanide complexes using ligand containing only one or two O-donors compare to five N-coordinating sites. The resultant multinuclear lanthanide complexes show interesting magnetic and spectroscopic features originating from different spatial arrangements of the metal ions. Alternating current (ac) susceptibility measurements of the two dysprosium complexes display frequency- and temperature-dependent out-of-phase signals in zero and 0.5 T direct current field, a typical characteristic feature of single-molecule magnet (SMM) behavior, indicating different energy reversal barriers due to different molecular topologies. Another aspect of this work is the occurrence of the not-so-common SMM behavior of the terbium complex, further confirmed by ac susceptibility measurement.

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.

Bearing Dislocation and Progression of Osteoarthritis After Mobile-bearing Unicompartmental Knee Arthroplasty Vary Between Asian and Western Patients: A Meta-analysis.

PubMed

Ro, Kyung-Han; Heo, Jae-Won; Lee, Dae-Hee

2018-05-01

Implant survivorship is reported to be lower and complications, particularly bearing dislocation, are reported to be more frequent in Asian than in Western patients with medial knee osteoarthritis (OA) undergoing Oxford® Phase III unicompartmental knee arthroplasty (UKA). To date, however, these complications have not been compared between these groups of patients. The purpose of this study was to perform a meta-analysis comparing the standardized incidence rates of (1) all-cause reoperation; (2) reoperation related to bearing dislocation; and (3) reoperation related to progression of lateral compartment arthritis in Asian and Western patients with medial knee OA who underwent Oxford Phase III UKA. We searched MEDLINE® (January 1, 1976, to May 31, 2017), EMBASE® (January 1, 1985, to May 31, 2017), and the Cochrane Library (January 1, 1987, to May 31, 2017) for studies that reported complications of Oxford Phase III UKAs. Studies were included if they reported reoperation rates attributable to bearing dislocation and/or progression of lateral knee OA after surgery with this implant. Twenty-seven studies were included in this systematic review and 16 studies with followups > 5 years were included in the meta-analysis. These rates were converted to standardized incidence rate (that is, reoperations per 100 observed component years) based on mean followup and number of involved knees in each study. After applying prespecified inclusion and exclusion criteria, the studies were categorized into two groups, Asian and Western, based on hospital location. Twenty-five studies, containing 3152 Asian patients and 5455 Western patients, were evaluated. Study quality was assessed by the modified Coleman Methodology score (MCMS). Although all studies were Level IV, their mean MCMS score was 66.92 (SD, 8.7; 95% confidence interval [CI], 63.5-70.3), indicating fair quality. Because the heterogeneity of all subgroup meta-analyses was high, a random-effects model was used with estimations using the restricted maximum likelihood method. There was no difference in the proportion of Asian patients versus Western patients undergoing reoperation for any cause calculated as 100 component observed years (1.022 of 3152 Asian patients; 95% CI, 0.810-1.235 versus 1.300 of 5455 Western patients; 95% CI, 1.067-1.534; odds ratio, 0.7839; 95% CI, 0.5323-1.1545; p = 0.178). The mean reoperation rate attributable to bearing dislocation per 100 observed years was higher in Asian than in Western patients (0.525; 95% CI, 0.407-0.643 versus 0.141; 95% CI, 0.116-0.166; odds ratio, 3.7378; 95% CI, 1.694-8.248; p = 0.001) Conversely, the mean reoperation rate attributable to lateral knee OA per 100 observed years was lower in Asian than in Western patients (0.093; 95% CI, 0.070-0.115 versus 0.298; 95% CI, 0.217-0.379; odds ratio, 0.3114; 95% CI, 0.0986-0.9840; p < 0.001). Although total reoperation rates did not differ in the two populations, reoperation for bearing dislocation was more likely to occur in Asian than in Western patients, whereas reoperation for lateral knee OA progression was more likely to occur in Western than in Asian patients after Oxford Phase III UKA. Although possible explanations for these findings may be hypothesized, additional randomized, prospective comparative studies are needed. However, better survival outcomes after UKA may require consideration of ethnicity and lifestyle choices in addition to traditional surgical technique and perioperative care. Level III, therapeutic study.

Cellulose-lanthanum hydroxide nanocomposite as a selective marker for detection of toxic copper

PubMed Central

2014-01-01

In this current report, a simple, reliable, and rapid method based on modifying the cellulose surface by doping it with different percentages of lanthanum hydroxide (i.e., 1% La(OH)3-cellulose (LC), 5% La(OH)3-cellulose (LC2), and 10% La(OH)3-cellulose (LC3)) was proposed as a selective marker for detection of copper (Cu(II)) in aqueous medium. Surface properties of the newly modified cellulose phases were confirmed by Fourier transform infrared spectroscopy, field emission scanning electron microscope, energy dispersive X-ray spectroscopy, X-ray diffraction, and X-ray photoelectron spectroscopic analysis. The effect of pH on the adsorption of modified cellulose phases for Cu(II) was evaluated, and LC3 was found to be the most selective for Cu(II) at pH 6.0. Other parameters, influencing the maximum uptake of Cu(II) on LC3, were also investigated for a deeper mechanistic understanding of the adsorption phenomena. Results showed that the adsorption capacity for Cu(II) was improved by 211% on the LC3 phase as compared to diethylaminoethyl cellulose phase after only 2 h contact time. Adsorption isotherm data established that the adsorption process nature was monolayer with a homogeneous adsorbent surface. Results displayed that the adsorption of Cu(II) onto the LC3 phase obeyed a pseudo-second-order kinetic model. Selectivity studies toward eight metal ions, i.e., Cd(II), Co(II), Cr(III), Cr(VI), Cu(II), Fe(III), Ni(II), and Zn(II), were further performed at the optimized pH value. Based on the selectivity study, it was found that Cu(II) is highly selective toward the LC3 phase. Moreover, the efficiency of the proposed method was supported by implementing it to real environmental water samples with adequate results. PMID:25258599

Impact of Dengue Vaccination on Serological Diagnosis: Insights From Phase III Dengue Vaccine Efficacy Trials

PubMed Central

Plennevaux, Eric; Moureau, Annick; Arredondo-García, José L; Villar, Luis; Pitisuttithum, Punnee; Tran, Ngoc H; Bonaparte, Matthew; Chansinghakul, Danaya; Coronel, Diana L; L’Azou, Maïna; Ochiai, R Leon; Toh, Myew-Ling; Noriega, Fernando; Bouckenooghe, Alain

2018-01-01

Abstract Background We previously reported that vaccination with the tetravalent dengue vaccine (CYD-TDV; Dengvaxia) may bias the diagnosis of dengue based on immunoglobulin M (IgM) and immunoglobulin G (IgG) assessments. Methods We undertook a post hoc pooled analysis of febrile episodes that occurred during the active surveillance phase (the 25 months after the first study injection) of 2 pivotal phase III, placebo-controlled CYD-TDV efficacy studies that involved ≥31000 children aged 2–16 years across 10 countries in Asia and Latin America. Virologically confirmed dengue (VCD) episode was defined with a positive test for dengue nonstructural protein 1 antigen or dengue polymerase chain reaction. Probable dengue episode was serologically defined as (1) IgM-positive acute- or convalescent-phase sample, or (2) IgG-positive acute-phase sample and ≥4-fold IgG increase between acute- and convalescent-phase samples. Results There were 1284 VCD episodes (575 and 709 in the CYD-TDV and placebo groups, respectively) and 17673 other febrile episodes (11668 and 6005, respectively). Compared with VCD, the sensitivity and specificity of probable dengue definition were 93.1% and 77.2%, respectively. Overall positive and negative predictive values were 22.9% and 99.5%, respectively, reflecting the much lower probability of correctly confirming probable dengue in a population including a vaccinated cohort. Vaccination-induced bias toward false-positive diagnosis was more pronounced among individuals seronegative at baseline. Conclusions Caution will be required when interpreting IgM and IgG data obtained during routine surveillance in those vaccinated with CYD-TDV. There is an urgent need for new practical, dengue-specific diagnostic algorithms now that CYD-TDV is approved in a number of dengue-endemic countries. Clinical Trials Registration NCT01373281 and NCT01374516. PMID:29300876

Impact of Dengue Vaccination on Serological Diagnosis: Insights From Phase III Dengue Vaccine Efficacy Trials.

PubMed

Plennevaux, Eric; Moureau, Annick; Arredondo-García, José L; Villar, Luis; Pitisuttithum, Punnee; Tran, Ngoc H; Bonaparte, Matthew; Chansinghakul, Danaya; Coronel, Diana L; L'Azou, Maïna; Ochiai, R Leon; Toh, Myew-Ling; Noriega, Fernando; Bouckenooghe, Alain

2018-04-03

We previously reported that vaccination with the tetravalent dengue vaccine (CYD-TDV; Dengvaxia) may bias the diagnosis of dengue based on immunoglobulin M (IgM) and immunoglobulin G (IgG) assessments. We undertook a post hoc pooled analysis of febrile episodes that occurred during the active surveillance phase (the 25 months after the first study injection) of 2 pivotal phase III, placebo-controlled CYD-TDV efficacy studies that involved ≥31000 children aged 2-16 years across 10 countries in Asia and Latin America. Virologically confirmed dengue (VCD) episode was defined with a positive test for dengue nonstructural protein 1 antigen or dengue polymerase chain reaction. Probable dengue episode was serologically defined as (1) IgM-positive acute- or convalescent-phase sample, or (2) IgG-positive acute-phase sample and ≥4-fold IgG increase between acute- and convalescent-phase samples. There were 1284 VCD episodes (575 and 709 in the CYD-TDV and placebo groups, respectively) and 17673 other febrile episodes (11668 and 6005, respectively). Compared with VCD, the sensitivity and specificity of probable dengue definition were 93.1% and 77.2%, respectively. Overall positive and negative predictive values were 22.9% and 99.5%, respectively, reflecting the much lower probability of correctly confirming probable dengue in a population including a vaccinated cohort. Vaccination-induced bias toward false-positive diagnosis was more pronounced among individuals seronegative at baseline. Caution will be required when interpreting IgM and IgG data obtained during routine surveillance in those vaccinated with CYD-TDV. There is an urgent need for new practical, dengue-specific diagnostic algorithms now that CYD-TDV is approved in a number of dengue-endemic countries. NCT01373281 and NCT01374516.

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

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

Dipeptidyl peptidase-IV inhibitor use associated with increased risk of ACE inhibitor-associated angioedema.

PubMed

Brown, Nancy J; Byiers, Stuart; Carr, David; Maldonado, Mario; Warner, Barbara Ann

2009-09-01

Dipeptidyl peptidase-IV (DPP-IV) inhibitors decrease degradation of the incretins. DPP-IV inhibitors also decrease degradation of peptides, such as substance P, that may be involved in the pathogenesis of angiotensin-converting enzyme (ACE) inhibitor-associated angioedema. This study tested the hypothesis that DPP-IV inhibition affects risk of clinical angioedema, by comparing the incidence of angioedema in patients treated with the DPP-IV inhibitor vildagliptin versus those treated with comparator in Phase III randomized clinical trials. Prospectively defined angioedema-related events were adjudicated in a blinded fashion by an internal medicine adjudication committee and expert reviewer. Concurrent ACE inhibitor or angiotensin receptor blocker exposure was ascertained from case report forms. Study drug exposure was ascertained from unblinded data from phase III studies. Odds ratios and 95% confidence intervals comparing angioedema risk in vildagliptin-treated and comparator-treated patients were calculated for the overall population and for patients taking ACE inhibitors or angiotensin receptor blockers, using both an analysis of pooled data and a meta-analysis (Peto method). Overall, there was no association between vildagliptin use and angioedema. Among individuals taking an ACE inhibitor, however, vildagliptin use was associated with an increased risk of angioedema (14 confirmed cases among 2754 vildagliptin users versus 1 case among 1819 comparator users: odds ratio 4.57 [95% confidence interval 1.57 to 13.28]) in the meta-analysis. Vildagliptin use may be associated with increased risk of angioedema among patients taking ACE inhibitors, although absolute risk is small. Physicians confronted with angioedema in a patient taking an ACE inhibitor and DPP-IV inhibitor should consider this possible drug-drug interaction.

Risk of renal failure with the non-vitamin K antagonist oral anticoagulants: systematic review and meta-analysis.

PubMed

Caldeira, Daniel; Gonçalves, Nilza; Pinto, Fausto J; Costa, João; Ferreira, Joaquim J

2015-07-01

Vitamin K antagonists (VKA)-related nephropathy is a novel entity characterized by acute kidney injury related to International Normalized Ratio supratherapeutic levels. Non-vitamin K antagonists oral anticoagulants (NOACs) have a predictable dose-response relationship and an improved safety profile. We hypothesized that these drugs do not have an increased risk of incident renal failure, which may be detrimental for the use of NOACs. Systematic review and meta-analysis of phase III randomized controlled trials (RCTs). Trials were searched through Medline, Cochrane Library and public assessment reports in August 2014. Primary outcome was renal failure. NOACs were evaluated against any comparator. Random-effects meta-analysis was performed by default, and pooled estimates were expressed as Risk Ratio (RR) and 95%CI. Heterogeneity was evaluated with I(2) test. Ten RCTs fulfilled inclusion criteria (one apixaban RCT, three dabigatran RCTs, and six rivaroxaban RCTs), enrolling 75 100 patients. Overall NOACs did not increase the risk of renal failure with an RR 0.96, 95%CI 0.88-1.05 compared with VKA or Low-molecular weight heparin (LMWH), without significant statistical heterogeneity (I(2)  = 3.5%). Compared with VKA, NOACs did not increase the risk of renal failure (RR 0.96, 95%CI 0.87-1.07; I(2)  = 17.8%; six RCTs). Rivaroxaban did not show differences in the incidence of renal failure compared with LMWH (RR 1.20, 95%CI 0.37-3.94; four trials), but there was an increased risk of creatinine elevation RR 1.25, 95%CI 1.08-1.45; I(2)  = 0%. NOACs had a similar risk of renal failure compared with VKA/LMWH in phase III RCTs. Post-marketing surveillance should be warranted. Copyright © 2015 John Wiley & Sons, Ltd.

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 strategy for the preparation of thioantimonates based on the concept of weak acids and corresponding strong bases.

PubMed

Anderer, Carolin; Delwa de Alarcón, Natalie; Näther, Christian; Bensch, Wolfgang

2014-12-15

By following a new synthetic approach, which is based on the in situ formation of a basic medium by the reaction between the strong base Sb(V)S4 (3-) and the weak acid H2 O, it was possible to prepare three layered thioantimonate(III) compounds of composition [TM(2,2'-bipyridine)3 ][Sb6 S10 ] (TM=Ni, Fe) and [Ni(4,4'-dimethyl-2,2'-bipyridine)3 ][Sb6 S10 ] under hydrothermal conditions featuring two different thioantimonate(III) network topologies. The antimony source, Na3 SbS4 ⋅ 9 H2 O, undergoes several decomposition reactions and produces the Sb(III) S3 species, which condenses to generate the layered anion. The application of transition-metal complexes avoids crystallization of dense phases. The reactions are very fast compared to conventional hydrothermal/solvothermal syntheses and are much less sensitive to changes of the reaction parameters. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Liquid-liquid extraction of neodymium(III) by dialkylphosphate ionic liquids from acidic medium: the importance of the ionic liquid cation.

PubMed

Rout, Alok; Kotlarska, Justyna; Dehaen, Wim; Binnemans, Koen

2013-10-21

The ionic liquids 1-hexyl-3-methylimidazolium bis(2-ethylhexyl)phosphate, [C6mim][DEHP], 1-hexyl-1-methylpyrrolidinium bis(2-ethylhexyl)phosphate, [C6mpyr][DEHP], and tetrabutylammonium bis(2-ethylhexyl)phosphate, [N4444][DEHP], were prepared and characterized using (1)H and (13)C NMR spectroscopy. The extraction behavior of neodymium(iii) from nitrate medium by these ionic liquids, diluted with the room temperature ionic liquids 1-hexyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide, [C6mim][NTf2], 1-hexyl-3-methylpyrrolidinium bis(trifluoromethylsulfonyl)imide, [C6mpyr][NTf2], and tributylmethylammonium bis(trifluoromethylsulfonyl)imide, [N1444][NTf2], was studied. The distribution ratio of neodymium(iii) was measured as a function of various parameters, such as pH, concentration of the ionic liquid extractant, nature of diluents, concentration of ionic liquid cations and nitrate anions in the aqueous phase. The extraction behavior was compared with that obtained for a solution of the molecular extractant bis(2-ethylhexyl)phosphoric acid (DEHPA) in an ionic liquid diluent. The extraction of neodymium(iii) in the ionic liquids [C6mim][DEHP] and [C6mpyr][DEHP] showed markedly different extraction properties in comparison with that of the quaternary ammonium analogue [N4444][DEHP], especially concerning the pH dependence of the extraction process. These results show that the extraction process can be tuned by the selection of the ionic liquid cation. The extraction experiments also included the trivalent rare-earth ions lanthanum(iii), cerium(iii), praseodymium(iii), ytterbium(iii) and yttrium(iii). Studies of the stripping behavior and the reusability of the ionic liquids were carried out, which indicate that the ionic liquids can be reused with no loss in activity.

Reduction in lipoprotein-associated apoC-III levels following volanesorsen therapy: phase 2 randomized trial results.

PubMed

Yang, Xiaohong; Lee, Sang-Rok; Choi, Yun-Seok; Alexander, Veronica J; Digenio, Andres; Yang, Qingqing; Miller, Yury I; Witztum, Joseph L; Tsimikas, Sotirios

2016-04-01

Elevated apoC-III levels predict increased cardiovascular risk when present on LDL and HDL particles. We developed novel high-throughput chemiluminescent ELISAs that capture apoB, lipoprotein (a) [Lp(a)], and apoA-I in plasma and then detect apoC-III on these individual lipoproteins as apoCIII-apoB, apoCIII-Lp(a), and apoCIII-apoAI complexes, respectively. We assessed the effects on these complexes of placebo or 100-300 mg volanesorsen, a generation 2.0+ antisense drug that targets apoC3 mRNA in patients with hypertriglyceridemia, including familial chylomicronemia syndrome (n = 3), volanesorsen monotherapy (n = 51), and as add-on to fibrate (n = 26), treated for 85 days and followed for 176 days. Compared with placebo, volanesorsen was associated with an 82.3 ± 11.7%, 81.3 ± 15.7%, and 80.8 ± 13.6% reduction in apoCIII-apoB, apoCIII-Lp(a), and apoCIII-apoA-I, respectively (300 mg dose;P< 0.001 for all), at day 92. Strong correlations in all assay measures were noted with total plasma apoC-III, chylomicron-apoC-III, and VLDL-apoC-III. In conclusion, novel high-throughput ELISAs were developed to detect lipoprotein-associated apoC-III, including for the first time on Lp(a). Volanesorsen uniformly lowers apoC-III on apoB-100, Lp(a), and apoA-I lipoproteins, and may be a potent agent to reduce triglycerides and cardiovascular risk mediated by apoC-III. Copyright © 2016 by the American Society for Biochemistry and Molecular Biology, Inc.

Capnogram slope and ventilation dead space parameters: comparison of mainstream and sidestream techniques.

PubMed

Balogh, A L; Petak, F; Fodor, G H; Tolnai, J; Csorba, Z; Babik, B

2016-07-01

Capnography may provide useful non-invasive bedside information concerning heterogeneity in lung ventilation, ventilation-perfusion mismatching and metabolic status. Although the capnogram may be recorded by mainstream and sidestream techniques, the capnogram indices furnished by these approaches have not previously been compared systematically. Simultaneous mainstream and sidestream time and volumetric capnography was performed in anaesthetized, mechanically ventilated patients undergoing elective heart surgery. Time capnography was used to assess the phase II (SII,T) and III slopes (SIII,T). The volumetric method was applied to estimate phase II (SII,V) and III slopes (SIII,V), together with the dead space values according to the Fowler (VDF), Bohr (VDB), and Enghoff (VDE) methods and the volume of CO2 eliminated per breath ([Formula: see text]). The partial pressure of end-tidal CO2 ([Formula: see text]) was registered. Excellent correlation and good agreement were observed in SIII,T measured by the mainstream and sidestream techniques [ratio=1.05 (sem 0.16), R(2)=0.92, P<0.0001]. Although the sidestream technique significantly underestimated [Formula: see text] and overestimated SIII,V [1.32 (0.28), R(2)=0.93, P<0.0001], VDF, VDB, and VDE, the agreement between the mainstream and sidestream techniques in the difference between VDE and VDB, reflecting the intrapulmonary shunt, was excellent [0.97 (0.004), R(2)=0.92, P<0.0001]. The [Formula: see text] exhibited good correlation and mild differences between the mainstream and sidestream approaches [0.025 (0.005) kPa]. Sidestream capnography provides adequate quantitative bedside information about uneven alveolar emptying and ventilation-perfusion mismatching, because it allows reliable assessments of the phase III slope, [Formula: see text] and intrapulmonary shunt. Reliable measurement of volumetric parameters (phase II slope, dead spaces, and eliminated CO2 volumes) requires the application of a mainstream device. © The Author 2016. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Capnogram slope and ventilation dead space parameters: comparison of mainstream and sidestream techniques

PubMed Central

Balogh, A. L.; Petak, F.; Fodor, G. H.; Tolnai, J.; Csorba, Z.; Babik, B.

2016-01-01

Background Capnography may provide useful non-invasive bedside information concerning heterogeneity in lung ventilation, ventilation–perfusion mismatching and metabolic status. Although the capnogram may be recorded by mainstream and sidestream techniques, the capnogram indices furnished by these approaches have not previously been compared systematically. Methods Simultaneous mainstream and sidestream time and volumetric capnography was performed in anaesthetized, mechanically ventilated patients undergoing elective heart surgery. Time capnography was used to assess the phase II (SII,T) and III slopes (SIII,T). The volumetric method was applied to estimate phase II (SII,V) and III slopes (SIII,V), together with the dead space values according to the Fowler (VDF), Bohr (VDB), and Enghoff (VDE) methods and the volume of CO2 eliminated per breath (VCO2). The partial pressure of end-tidal CO2 (PETCO2) was registered. Results Excellent correlation and good agreement were observed in SIII,T measured by the mainstream and sidestream techniques [ratio=1.05 (sem 0.16), R2=0.92, P<0.0001]. Although the sidestream technique significantly underestimated VCO2 and overestimated SIII,V [1.32 (0.28), R2=0.93, P<0.0001], VDF, VDB, and VDE, the agreement between the mainstream and sidestream techniques in the difference between VDE and VDB, reflecting the intrapulmonary shunt, was excellent [0.97 (0.004), R2=0.92, P<0.0001]. The PETCO2 exhibited good correlation and mild differences between the mainstream and sidestream approaches [0.025 (0.005) kPa]. Conclusions Sidestream capnography provides adequate quantitative bedside information about uneven alveolar emptying and ventilation–perfusion mismatching, because it allows reliable assessments of the phase III slope, PETCO2 and intrapulmonary shunt. Reliable measurement of volumetric parameters (phase II slope, dead spaces, and eliminated CO2 volumes) requires the application of a mainstream device. PMID:27317710

The Utilization of the Microflora Indigenous to and Present in Oil-Bearing Formations to Selectively Plug the More Porous Zones Thereby Increasing Oil Recovery During Waterflooding

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

Brown, Lewis R.; Byrnes, Martin J.; Stephens, James O.

This project was designed to demonstrate that a microbially enhanced oil recovery process (MEOR), developed in part under DOE Contract No. DE-AC22-90BC14665, will increase oil recovery from fluvial dominated deltaic oil reservoirs. The process involves stimulating the in-situ indigenous microbial population in the reservoir to grow in the more permeable zones, thus diverting flow to other areas of the reservoir, thereby increasing the effectiveness of the waterflood. This five and a half year project is divided into three phases, Phase I, Planning and Analysis (9 months), Phase II, Implementation (45 months), and Phase III, Technology Transfer (12 months). Phase Imore » was completed and reported in the first annual report. This fifth annual report covers the completion of Phase II and the first six months of Phase III.« less

Comparative evaluation of serum C-reactive protein levels in chronic and aggressive periodontitis patients and association with periodontal disease severity

PubMed Central

Goyal, Lata; Bey, Afshan; Gupta, N. D.; Sharma, Vivek Kumar

2014-01-01

Objective: C-reactive protein (CRP) is an acute-phase reactant and has been proved to be a significant predictor of future cardiovascular events. Recent studies have demonstrated a correlation between periodontitis and elevated CRP levels. However, most of the studies have focused on chronic periodontitis and very few studies are done in patients with aggressive periodontitis. The aim of this study was to determine and compare the relative levels of serum CRP in aggressive and chronic periodontitis patients. Materials and Methods: A total of 75 systemically healthy subjects were divided into three groups: Group I, nonperiodontitis subjects; group II, chronic generalized periodontitis patients and group III, generalized aggressive periodontitis patients. All participants were subjected to quantitative CRP analysis using enzyme-linked immunosorbent assay. Results: Mean CRP levels were significantly greater in both group II and III as compared to group I and group III having greater level than group II. Furthermore, CRP levels positively correlated with the amount of periodontal destruction as measured by probing depth and clinical attachment loss. Conclusion: The present study indicates a positive correlation between CRP and periodontal disease severity with particular concern in younger individuals that could be a possible underlying pathway in the association between periodontal disease and the observed higher risk for cardiovascular disease in periodontitis patients. PMID:25395764

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.

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

Wu, Tao; Kukkadapu, Ravi K.; Griffin, Aron M.

Fe(III)-oxides and Fe(III)-bearing phyllosilicates are the two major iron sources utilized as electron acceptors by dissimilatory iron-reducing bacteria (DIRB) in anoxic soils and sediments. Although there have been many studies of microbial Fe(III)-oxide and Fe(III)-phyllosilicate reduction with both natural and specimen materials, no controlled experimental information is available on the interaction between these two phases when both are available for microbial reduction. In this study, the model DIRB Geobacter sulfurreducens was used to examine the pathways of Fe(III) reduction in Fe(III)-oxide stripped subsurface sediment that was coated with different amounts of synthetic high surface area goethite. Cryogenic (12K) 57Fe Mössbauermore » spectroscopy was used to determine changes in the relative abundances of Fe(III)-oxide, Fe(III)-phyllosilicate, and phyllosilicate-associated Fe(II) (Fe(II)-phyllosilicate) in bioreduced samples. Analogous Mössbauer analyses were performed on samples from abiotic Fe(II) sorption experiments in which sediments were exposed to a quantity of exogenous soluble Fe(II) (FeCl22H2O) comparable to the amount of Fe(II) produced during microbial reduction. A Fe partitioning model was developed to analyze the fate of Fe(II) and assess the potential for abiotic Fe(II)-catalyzed reduction of Fe(III)-phyllosilicatesilicates. The microbial reduction experiments indicated that although reduction of Fe(III)-oxide accounted for virtually all of the observed bulk Fe(III) reduction activity, there was no significant abiotic electron transfer between oxide-derived Fe(II) and Fe(III)-phyllosilicatesilicates, with 26-87% of biogenic Fe(II) appearing as sorbed Fe(II) in the Fe(II)-phyllosilicate pool. In contrast, the abiotic Fe(II) sorption experiments showed that 41 and 24% of the added Fe(II) engaged in electron transfer to Fe(III)-phyllosilicate surfaces in synthetic goethite-coated and uncoated sediment. Differences in the rate of Fe(II) addition and system redox potential may account for the microbial and abiotic reaction systems. Our experiments provide new insight into pathways for Fe(III) reduction in mixed Fe(III)-oxide/Fe(III)-phyllosilicate assemblages, and provide key mechanistic insight for interpreting microbial reduction experiments and field data from complex natural soils and sediments.« less

Five-year survival rates for treatment-naive patients with advanced melanoma who received ipilimumab plus dacarbazine in a phase III trial.

PubMed

Maio, Michele; Grob, Jean-Jacques; Aamdal, Steinar; Bondarenko, Igor; Robert, Caroline; Thomas, Luc; Garbe, Claus; Chiarion-Sileni, Vanna; Testori, Alessandro; Chen, Tai-Tsang; Tschaika, Marina; Wolchok, Jedd D

2015-04-01

There is evidence from nonrandomized studies that a proportion of ipilimumab-treated patients with advanced melanoma experience long-term survival. To demonstrate a long-term survival benefit with ipilimumab, we evaluated the 5-year survival rates of patients treated in a randomized, controlled phase III trial. A milestone survival analysis was conducted to capture the 5-year survival rate of treatment-naive patients with advanced melanoma who received ipilimumab in a phase III trial. Patients were randomly assigned 1:1 to receive ipilimumab at 10 mg/kg plus dacarbazine (n = 250) or placebo plus dacarbazine (n = 252) at weeks 1, 4, 7, and 10 followed by dacarbazine alone every 3 weeks through week 22. Eligible patients could receive maintenance ipilimumab or placebo every 12 weeks beginning at week 24. A safety analysis was conducted on patients who survived at least 5 years and continued to receive ipilimumab as maintenance therapy. The 5-year survival rate was 18.2% (95% CI, 13.6% to 23.4%) for patients treated with ipilimumab plus dacarbazine versus 8.8% (95% CI, 5.7% to 12.8%) for patients treated with placebo plus dacarbazine (P = .002). A plateau in the survival curve began at approximately 3 years. In patients who survived at least 5 years and continued to receive ipilimumab, grade 3 or 4 immune-related adverse events were observed exclusively in the skin. The additional survival benefit of ipilimumab plus dacarbazine is maintained with twice as many patients alive at 5 years compared with those who initially received placebo plus dacarbazine. These results demonstrate a durable survival benefit with ipilimumab in advanced melanoma. © 2015 by American Society of Clinical Oncology.

Five-Year Survival Rates for Treatment-Naive Patients With Advanced Melanoma Who Received Ipilimumab Plus Dacarbazine in a Phase III Trial

PubMed Central

Maio, Michele; Grob, Jean-Jacques; Aamdal, Steinar; Bondarenko, Igor; Robert, Caroline; Thomas, Luc; Garbe, Claus; Chiarion-Sileni, Vanna; Testori, Alessandro; Chen, Tai-Tsang; Tschaika, Marina; Wolchok, Jedd D.

2015-01-01

Purpose There is evidence from nonrandomized studies that a proportion of ipilimumab-treated patients with advanced melanoma experience long-term survival. To demonstrate a long-term survival benefit with ipilimumab, we evaluated the 5-year survival rates of patients treated in a randomized, controlled phase III trial. Patients and Methods A milestone survival analysis was conducted to capture the 5-year survival rate of treatment-naive patients with advanced melanoma who received ipilimumab in a phase III trial. Patients were randomly assigned 1:1 to receive ipilimumab at 10 mg/kg plus dacarbazine (n = 250) or placebo plus dacarbazine (n = 252) at weeks 1, 4, 7, and 10 followed by dacarbazine alone every 3 weeks through week 22. Eligible patients could receive maintenance ipilimumab or placebo every 12 weeks beginning at week 24. A safety analysis was conducted on patients who survived at least 5 years and continued to receive ipilimumab as maintenance therapy. Results The 5-year survival rate was 18.2% (95% CI, 13.6% to 23.4%) for patients treated with ipilimumab plus dacarbazine versus 8.8% (95% CI, 5.7% to 12.8%) for patients treated with placebo plus dacarbazine (P = .002). A plateau in the survival curve began at approximately 3 years. In patients who survived at least 5 years and continued to receive ipilimumab, grade 3 or 4 immune-related adverse events were observed exclusively in the skin. Conclusion The additional survival benefit of ipilimumab plus dacarbazine is maintained with twice as many patients alive at 5 years compared with those who initially received placebo plus dacarbazine. These results demonstrate a durable survival benefit with ipilimumab in advanced melanoma. PMID:25713437

The Value of Botox-A in Acute Radiation Proctitis: Results From a Phase I/II Study Using a Three-Dimensional Scoring System

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

Vuong, Te, E-mail: tvuong@jgh.mcgill.ca; Waschke, Kevin; Niazi, Tamim

Purpose: Acute radiation proctitis (ARP) is a common side effect of pelvic radiotherapy, and its management is challenging in daily practice. The present phase I/II study evaluates the safety and efficacy of the botulinum toxin A (BTX-A) in ARP treatment for rectal cancer patients undergoing neoadjuvant high-dose-rate endorectal brachytherapy (HDREBT). Methods and Materials: Fifteen patients, treated with neoadjuvant HDREBT, 26-Gy in 4 fractions, received the study treatment that consisted of a single injection of BTX-A into the rectal wall. The injection was performed post-HDREBT and prior to the development of ARP. The control group, 20 such patients, did not receivemore » the BTX-A injection. Both groups had access to standard treatment with hydrocortisone rectal aerosol foam (Cortifoam) and anti-inflammatory and narcotic medication. The ARP was clinically evaluated by self-administered daily questionnaires using visual analog scores to document frequency and urgency of bowel movements, rectal burning/tenesmus, and pain symptoms before and after HDREBT. Results: At the time of this analysis, there was no observed systemic toxicity. Patient compliance with the self-administered questionnaire was 100% from week 1 to 4, 70% during week 5, and 40% during week 6. The maximum tolerated dose was established at the 100-U dose level, and noticeable mean differences were observed in bowel frequency (p = 0.016), urgency (p = 0.007), and pain (p = 0.078). Conclusions: This study confirms the feasibility and efficacy of BTX-A intervention at 100-U dose level for study patients compared to control patients. A phase III study with this dose level is planned to validate these results.« less

Efficacy and Safety of Risedronate in Osteoporosis Subjects with Comorbid Diabetes, Hypertension, and/or Dyslipidemia: A Post Hoc Analysis of Phase III Trials Conducted in Japan.

PubMed

Inoue, Daisuke; Muraoka, Ryoichi; Okazaki, Ryo; Nishizawa, Yoshiki; Sugimoto, Toshitsugu

2016-02-01

Many osteoporotics have comorbid diabetes mellitus (DM), hypertension (HT), and dyslipidemia (DL). However, whether such comorbidities alter response to anti-osteoporotic treatment is unknown. We did post hoc analyses of combined data from three risedronate Japanese phase III trials to determine whether the presence of DM, HT, or DL affects its efficacy and safety. Data from 885 subjects who received 48-week treatment with risedronate were collected and combined from the three phase III trials. They were divided into two groups by the presence or absence of comorbidities: DM (n = 53) versus non-DM (n = 832); HT (n = 278) versus non-HT (n = 607); and DL (n = 292) versus non-DL (n = 593). Bone mineral density (BMD), urinary type 1 collagen N-telopeptide (uNTX), and serum bone-specific alkaline phosphatase (BAP) were measured at baseline and sequentially until 48 weeks. BMD or bone markers were not different between any of the two groups. Overall, BMD was increased by 5.52%, and uNTX and BAP were decreased by 35.4 and 33.8%, respectively. Some bone markers were slightly lower in DM and DL subjects, but the responses to risedronate were not significantly different. Statin users had lower uNTX and BAP, but showed no difference in the treatment response. All the other medications had no apparent effect. Adverse event incidence was marginally higher in DL compared with non-DL (Relative risk 1.06; 95% confidence interval 1.01-1.11), but was not related to increase in any specific events. Risedronate shows consistent safety and efficacy in suppressing bone turnover and increasing BMD in osteoporosis patients with comorbid DM, HT, and/or DL.

Phase III randomized clinical trial comparing tremelimumab with standard-of-care chemotherapy in patients with advanced melanoma.

PubMed

Ribas, Antoni; Kefford, Richard; Marshall, Margaret A; Punt, Cornelis J A; Haanen, John B; Marmol, Maribel; Garbe, Claus; Gogas, Helen; Schachter, Jacob; Linette, Gerald; Lorigan, Paul; Kendra, Kari L; Maio, Michele; Trefzer, Uwe; Smylie, Michael; McArthur, Grant A; Dreno, Brigitte; Nathan, Paul D; Mackiewicz, Jacek; Kirkwood, John M; Gomez-Navarro, Jesus; Huang, Bo; Pavlov, Dmitri; Hauschild, Axel

2013-02-10

In phase I/II trials, the cytotoxic T lymphocyte-associated antigen-4-blocking monoclonal antibody tremelimumab induced durable responses in a subset of patients with advanced melanoma. This phase III study evaluated overall survival (OS) and other safety and efficacy end points in patients with advanced melanoma treated with tremelimumab or standard-of-care chemotherapy. Patients with treatment-naive, unresectable stage IIIc or IV melanoma were randomly assigned at a ratio of one to one to tremelimumab (15 mg/kg once every 90 days) or physician's choice of standard-of-care chemotherapy (temozolomide or dacarbazine). In all, 655 patients were enrolled and randomly assigned. The test statistic crossed the prespecified futility boundary at second interim analysis after 340 deaths, but survival follow-up continued. At final analysis with 534 events, median OS by intent to treat was 12.6 months (95% CI, 10.8 to 14.3) for tremelimumab and 10.7 months (95% CI, 9.36 to 11.96) for chemotherapy (hazard ratio, 0.88; P = .127). Objective response rates were similar in the two arms: 10.7% in the tremelimumab arm and 9.8% in the chemotherapy arm. However, response duration (measured from date of random assignment) was significantly longer after tremelimumab (35.8 v 13.7 months; P = .0011). Diarrhea, pruritus, and rash were the most common treatment-related adverse events in the tremelimumab arm; 7.4% had endocrine toxicities. Seven deaths in the tremelimumab arm and one in the chemotherapy arm were considered treatment related by either investigators or sponsor. This study failed to demonstrate a statistically significant survival advantage of treatment with tremelimumab over standard-of-care chemotherapy in first-line treatment of patients with metastatic melanoma.

A phase I/II randomized, controlled, clinical trial for assessment of the efficacy and safety of β-D-mannuronic acid in rheumatoid arthritis patients.

PubMed

Ahmadi, Hossein; Jamshidi, Ahmad Reza; Gharibdoost, Farhad; Mahmoudi, Mahdi; Rastkari, Noushin; Mostafaei, Shayan; Fattahi, Mohammad Javad; Vojdanian, Mahdi; Cuzzocrea, Salvatore; Rehm, Bernd H A; Matsuo, Hidenori; Hosseini, Mostafa; Aghazadeh, Zahra; Mortazavi-Jahromi, Seyed Shahabeddin; Mirshafiey, Abbas

2018-06-01

Following the potent efficacy of β-D-mannuronic acid (M2000) in phase I/II trial in ankylosing spondylitis patients, the present clinical trial was conducted to evaluate the efficacy, safety, and tolerability of this novel drug in rheumatoid arthritis (RA) patients who had inadequate response to conventional therapy. The study was a 12-week randomized, controlled, phase I/II clinical trial with two treatment arms: M2000 and conventional treatment. Patients who had RA according to the modified American College of Rheumatology (ACR) criteria, with active disease at baseline also inadequate response to conventional therapy, were enrolled in this study. M2000 was administrated at a dose of two capsules (500 mg) per day orally during a period of 12 weeks. The primary endpoint was the proportion of patients fulfilling the ACR 20% improvement criteria after 12 weeks of M2000 therapy. Moreover, the patients were also followed up for safety. There were no statistically significant differences between treatment and conventional groups at baseline characteristics. The ACR20 response rate was significantly higher among M2000-treated patients than conventional-treated control, so that 74% of patients in treatment group showed an ACR20 response after 12 weeks of M2000 therapy (74 versus 16%; P = 0.011). 10% of M2000-treated patients and 57.1% of conventional-treated patient's adverse events occurred during this study. Treatment with M2000 in combination with conventional therapy showed a significantly superior efficacy along with a high safety profile compared to conventional-treated patients. Thereby, M2000 might be suggested as a suitable option in the treatment of RA.

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

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

Correlation of cetuximab-induced skin rash and outcomes of solid tumor patients treated with cetuximab: a systematic review and meta-analysis.

PubMed

Abdel-Rahman, Omar; Fouad, Mona

2015-02-01

We performed a systematic review and meta-analysis of the correlation between cetuximab-induced skin rash and outcomes of solid tumor patients treated with cetuximab. Eligible studies included phase I, II and III trials of patients with solid tumors on cetuximab; describing events of skin rash and correlating skin rash with overall survival (OS), progression free survival (PFS) and/or overall response rate (ORR). Our search strategy yielded 409 potentially relevant citations on CETUXIMAB from Pubmed/Medline, CENTRAL Cochrane registry and ASCO meeting library. After exclusion of ineligible studies, a total of 13 clinical trials were considered eligible for the meta-analysis, including 4 phase III trials, 8 phase II trials and one phase I trial. The occurrence of cetuximab-induced rash in patients was highly associated with improvements in PFS (HR=0.74; 95% CI: 0.63-0.86, P<0.0002), OS (HR=0.60; 95% CI: 0.47-0.76, P<0.0001), and ORR (RR=1.51, 95% CI: 1.26-1.81, P<0.00001), as compared to patients without rash. Exploratory subgroup analysis showed no effect of tumor types on the RR of ORR. Our meta-analysis has demonstrated that cetuximab-induced rash is associated with a significantly improved OS, PFS and ORR. Cetuximab-induced skin rash may represent a prognostic factor in patients with advanced solid tumors. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Influence of crystal allomorph and crystallinity on the products and behavior of cellulose during fast pyrolysis

DOE PAGES

Mukarakate, Calvin; Mittal, Ashutosh; Ciesielski, Peter N.; ...

2016-07-19

Here, cellulose is the primary biopolymer responsible for maintaining the structural and mechanical integrity of cell walls and, during the fast pyrolysis of biomass, may be restricting cell wall expansion and inhibiting phase transitions that would otherwise facilitate efficient escape of pyrolysis products. Here, we test whether modifications in two physical properties of cellulose, its crystalline allomorph and degree of crystallinity, alter its performance during fast pyrolysis. We show that both crystal allomorph and relative crystallinity of cellulose impact the slate of primary products produced by fast pyrolysis. For both cellulose-I and cellulose-II, changes in crystallinity dramatically impact the fastmore » pyrolysis product portfolio. In both cases, only the most highly crystalline samples produced vapors dominated by levoglucosan. Cellulose-III, on the other hand, produces largely the same slate of products regardless of its relative crystallinity and produced as much or more levoglucosan at all crystallinity levels compared to cellulose-I or II. In addition to changes in products, the different cellulose allomorphs affected the viscoelastic properties of cellulose during rapid heating. Real-time hot-stage pyrolysis was used to visualize the transition of the solid material through a molten phase and particle shrinkage. SEM analysis of the chars revealed additional differences in viscoelastic properties and molten phase behavior impacted by cellulose crystallinity and allomorph. Regardless of relative crystallinity, the cellulose-III samples displayed the most obvious evidence of having transitioned through a molten phase.« less

Varenicline: a novel pharmacotherapy for smoking cessation.

PubMed

Jiménez-Ruiz, Carlos; Berlin, Ivan; Hering, Thomas

2009-07-09

Varenicline is an orally administered small molecule with partial agonist activity at the alpha4beta2 nicotinic acetylcholine receptor. Varenicline was approved by both the US FDA and the European Medicines Agency of the EU in 2006 as an aid to smoking cessation. Subsequently, varenicline has been approved in over 80 other countries. Varenicline is almost entirely absorbed following oral administration, and absorption is unaffected by food, smoking or the time of day. Varenicline undergoes only minimal metabolism and approximately 90% of the drug is excreted in the urine unchanged. Varenicline has a mean elimination half-life after repeated administration of approximately 24 hours in smokers. The area under the plasma concentration-time curve is increased in patients with moderate or severe renal failure. No clinically relevant varenicline-drug interactions have been identified. In two identical, randomized, double-blind, phase III clinical trials in healthy, motivated-to-quit, mainly Caucasian smokers aged 18-75 years in the US, 12 weeks of treatment with varenicline 1 mg twice daily was associated with significantly higher abstinence rates over weeks 9-12 than sustained-release bupropion 150 mg twice daily or placebo. In a separate phase III trial, an additional 12 weeks of treatment in smokers achieving abstinence in the first 12 weeks was associated with greater abstinence through to week 52 than placebo treatment. Varenicline treatment was also associated with significantly higher rates of abstinence than placebo treatment in randomized, double-blind, clinical trials in smokers in China, Japan, Korea, Singapore, Taiwan and Thailand. In a randomized, open-label, multi-national, phase III trial, varenicline treatment was associated with a significantly higher rate of abstinence than transdermal nicotine-replacement therapy. In these trials, varenicline treatment was associated with lower urge to smoke and satisfaction from smoking in relapsers than placebo or active comparators. In the two US phase III trials, 12 weeks of treatment with varenicline 1 mg twice daily had an acceptable safety and tolerability profile. Nausea and abnormal dreams were the most common adverse events that occurred in more varenicline than placebo recipients. The incidence and prevalence of nausea were greatest in weeks 1 and 2 of treatment, and declined thereafter. The prevalence of early adverse effects can be reduced by individual dose titration. Adverse events associated with varenicline therapy have been reported in post-marketing surveillance, including neuropsychiatric events such as depressed mood, agitation, changes in behaviour, suicidal ideation and suicide. Currently, it is unclear whether the association of varenicline therapy with these adverse events is causal, coincidental or related to smoking cessation. Given the greater efficacy of varenicline compared with other pharmacotherapies, and the high risk of morbidity and mortality associated with continued smoking, varenicline is a valuable pharmacological aid to smoking cessation.

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

PubMed

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

2016-09-01

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

Formation, Phase, and Elemental Composition of Micro- and Nano-Dimensional Particles of the Fe-Ti System

NASA Astrophysics Data System (ADS)

Dresvyannikov, A. F.; Kolpakov, M. E.

2018-05-01

X-ray fluorescence, X-ray phase analysis, and transmission Mössbauer and NGR spectrometry are used to study the formation, phase, and elemental composition of Fe-Ti particles. The interaction between Fe(III) ions and dispersed titanium in an aqueous solution containing chloride ions and HF is studied. It is shown that the resulting Fe-Ti samples are a set of core-shell microparticles with titanium cores coated with micro- and nanosized α-Fe nucleation centers with the thinness outer layer of iron(III) oxide characterized by a developed surface.

Validation of the phase II feasibility study in a palliative care setting: gastrografin in malignant bowel obstruction.

PubMed

Lee, Cindy; Vather, Ryash; O'Callaghan, Anne; Robinson, Jackie; McLeod, Briar; Findlay, Michael; Bissett, Ian

2013-12-01

Malignant bowel obstruction (MBO) is common in patients with advanced cancer. To perform a phase II study to assess the feasibility of conducting a phase III trial investigating the therapeutic value of gastrografin in MBO. Randomized double-blinded placebo-controlled feasibility study. Participants received 100 mL of either gastrografin or placebo. Over 8 months, 57 patients were screened and 9 enrolled (15.8% recruitment rate). Of the 9 enrolled, 4 received gastrografin (with 2 completing assessment) and 5 received placebo (with 4 completing assessment). It is not feasible to conduct a phase III trial using the same study protocol. This study validates the use of the phase II feasibility study to assess protocol viability in a palliative population prior to embarking on a larger trial.

Indirect Treatment Comparisons of Ibrutinib Versus Physician's Choice and Idelalisib Plus Ofatumumab in Patients With Previously Treated Chronic Lymphocytic Leukemia.

PubMed

Sorensen, Sonja; Wildgust, Mark; Sengupta, Nishan; Trambitas, Cristina; Diels, Joris; van Sanden, Suzy; Xu, Yingxin; Dorman, Emily

2017-01-01

Treatment options for patients with relapsed or refractory chronic lymphocytic leukemia (R/R CLL) are limited. Until recently, few effective treatment options existed, and even with the advent of new agents, studies evaluating comparative efficacy are scarce. In the Ibrutinib Versus Ofatumumab in Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia (RESONATE) Phase III study, ibrutinib, an oral, once-a-day, first-in-class covalent Bruton tyrosine kinase inhibitor, improved progression-free survival (PFS) and overall survival (OS) compared with ofatumumab (PFS hazard ratio [HR] = 0.106 and OS HR = 0.369 [adjusted for crossover] at a median of 16 months' follow-up). We sought to establish the relative efficacy of ibrutinib versus other treatment options for patients with R/R CLL using indirect comparison methods. A systematic literature review was conducted to identify clinical trials sharing a common treatment arm with the RESONATE Phase III trial such that a network meta-analysis or indirect treatment comparisons (ITCs) could be conducted. Two trials were identified, each using the same comparator (ofatumumab) as the RESONATE study. Two pairwise ITCs were conducted using the Bucher method to establish the relative treatment efficacy of ibrutinib versus (1) idelalisib plus ofatumumab in the first study and (2) physician's choice, defined as a mix of therapies commonly used in R/R CLL, in the second study. Odds ratios for these ITCs were calculated for overall response rate (ORR) and HRs for PFS and OS. A strong and consistent trend of superiority for ibrutinib was observed via these ITC models with idelalisib plus ofatumumab and physician's choice for ORR, PFS, and OS. Ibrutinib revealed prolonged PFS and OS versus comparators (PFS HR = 0.06; 95% CI, 0.04-0.11; and OS HR = 0.25; 95% CI, 0.12-0.54), physician's choice (PFS HR = 0.41; 95% CI, 0.25-0.66; and OS HR = 0.50; 95% CI, 0.23-1.08), and idelalisib plus ofatumumab. These findings were robust and continued to favor ibrutinib when adjusting (where appropriate) for underlying differences in patient population between the trials. Some trial differences were not accounted for in the models and thus some limitations remain; however, consistency of results supports the overall findings. In a randomized Phase III study, ibrutinib significantly improved ORR, PFS, and OS in patients with R/R CLL versus ofatumumab. In ITC models that used ofatumumab as the common comparator, ibrutinib appears to have higher ORR and longer PFS and OS versus both idelalisib plus ofatumumab and physician's choice. In the absence of head-to-head studies and taking into consideration inherent limitations of ITCs, these models provide useful estimates of comparative efficacy. Copyright © 2017 Elsevier HS Journals, Inc. All rights reserved.

Herpes Zoster and Tofacitinib: Clinical Outcomes and the Risk of Concomitant Therapy

PubMed Central

Curtis, Jeffrey R.; Lindsey, Stephen; Tanaka, Yoshiya; Yamaoka, Kunihiro; Valdez, Hernan; Hirose, Tomohiro; Nduaka, Chudy I.; Wang, Lisy; Mendelsohn, Alan M.; Fan, Haiyun; Chen, Connie; Bananis, Eustratios

2017-01-01

Objective Patients with rheumatoid arthritis (RA) are at increased risk of herpes zoster (HZ), and the risk appears to be increased in patients treated with tofacitinib. The aim of this study was to evaluate whether concomitant treatment with conventional synthetic disease‐modifying antirheumatic drugs (csDMARDs) or glucocorticoids (GCs) contributes to the increased risk of HZ in RA patients treated with tofacitinib. Methods HZ cases were identified from the databases of 2 phase I, 9 phase II, 6 phase III, and 2 long‐term extension studies of tofacitinib in RA patients. Crude incidence rates (IRs) of all HZ events (serious and nonserious) per 100 patient‐years (with 95% confidence intervals [95% CIs]) were calculated for unique patients. Within phase III studies, we described HZ rates according to concomitant csDMARD treatment and baseline GC use. A multivariable Cox proportional hazards regression model was used to evaluate HZ risk factors across studies. Results Across all studies (6,192 patients; 16,839 patient‐years), HZ was reported in 636 tofacitinib‐treated patients (IR 4.0, 95% CI 3.7–4.4). In most cases (93%), HZ was classified as nonserious, and the majority of patients (94%) had involvement of only 1 dermatome. HZ IRs varied across regions, from 2.4 (95% CI 2.0–2.9) in Eastern Europe to 8.0 (95% CI 6.6–9.6) in Japan and 8.4 (95% CI 6.4–10.9) in Korea. Within phase III studies, HZ IRs varied according to tofacitinib dose, background csDMARD treatment, and baseline use of GCs. The IRs were numerically lowest for monotherapy with tofacitinib 5 mg twice daily without GCs (IR 0.56 [95% CI 0.07–2.01]) and highest for tofacitinib 10 mg twice daily with csDMARDs and GCs (IR 5.44 [95% CI 3.72–7.68]). Age, GC use, tofacitinib dose, and enrollment within Asia were independent risk factors for HZ. Conclusion Patients receiving treatment with tofacitinib and GCs appear to have a greater risk of developing HZ compared with patients receiving tofacitinib monotherapy without GCs. PMID:28845604

Herpes Zoster and Tofacitinib: Clinical Outcomes and the Risk of Concomitant Therapy.

PubMed

Winthrop, Kevin L; Curtis, Jeffrey R; Lindsey, Stephen; Tanaka, Yoshiya; Yamaoka, Kunihiro; Valdez, Hernan; Hirose, Tomohiro; Nduaka, Chudy I; Wang, Lisy; Mendelsohn, Alan M; Fan, Haiyun; Chen, Connie; Bananis, Eustratios

2017-10-01

Patients with rheumatoid arthritis (RA) are at increased risk of herpes zoster (HZ), and the risk appears to be increased in patients treated with tofacitinib. The aim of this study was to evaluate whether concomitant treatment with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) or glucocorticoids (GCs) contributes to the increased risk of HZ in RA patients treated with tofacitinib. HZ cases were identified from the databases of 2 phase I, 9 phase II, 6 phase III, and 2 long-term extension studies of tofacitinib in RA patients. Crude incidence rates (IRs) of all HZ events (serious and nonserious) per 100 patient-years (with 95% confidence intervals [95% CIs]) were calculated for unique patients. Within phase III studies, we described HZ rates according to concomitant csDMARD treatment and baseline GC use. A multivariable Cox proportional hazards regression model was used to evaluate HZ risk factors across studies. Across all studies (6,192 patients; 16,839 patient-years), HZ was reported in 636 tofacitinib-treated patients (IR 4.0, 95% CI 3.7-4.4). In most cases (93%), HZ was classified as nonserious, and the majority of patients (94%) had involvement of only 1 dermatome. HZ IRs varied across regions, from 2.4 (95% CI 2.0-2.9) in Eastern Europe to 8.0 (95% CI 6.6-9.6) in Japan and 8.4 (95% CI 6.4-10.9) in Korea. Within phase III studies, HZ IRs varied according to tofacitinib dose, background csDMARD treatment, and baseline use of GCs. The IRs were numerically lowest for monotherapy with tofacitinib 5 mg twice daily without GCs (IR 0.56 [95% CI 0.07-2.01]) and highest for tofacitinib 10 mg twice daily with csDMARDs and GCs (IR 5.44 [95% CI 3.72-7.68]). Age, GC use, tofacitinib dose, and enrollment within Asia were independent risk factors for HZ. Patients receiving treatment with tofacitinib and GCs appear to have a greater risk of developing HZ compared with patients receiving tofacitinib monotherapy without GCs. © 2017 The Authors. Arthritis & Rheumatology published by Wiley Periodicals, Inc. on behalf of American College of Rheumatology.

Herpes Zoster and Tofacitinib Therapy in Patients With Rheumatoid Arthritis

PubMed Central

Winthrop, Kevin L; Yamanaka, Hisashi; Valdez, Hernan; Mortensen, Eric; Chew, Robert; Krishnaswami, Sriram; Kawabata, Thomas; Riese, Richard

2014-01-01

Objective Patients with rheumatoid arthritis (RA) are at increased risk for herpes zoster (HZ) (i.e., shingles). The aim of this study was to determine whether treatment with tofacitinib increases the risk of HZ in patients with RA. Methods HZ cases were identified as those reported by trial investigators from the databases of the phase II, phase III, and long-term extension (LTE) clinical trials in the Tofacitinib RA Development Program. Crude incidence rates (IRs) of HZ per 100 patient-years (with 95% confidence intervals [95% CIs]) were calculated by exposure group. Logistic regression analyses were performed to evaluate potential risk factors for HZ (e.g., age, prednisone use). Results Among 4,789 participants, 239 were identified as having tofacitinib-associated HZ during the phase II, phase III, and LTE trials, of whom 208 (87%) were female and whose median age was 57 years (range 21–75 years). One HZ case (0.4%) was multidermatomal; none of the cases involved visceral dissemination or death. Twenty-four patients with HZ (10%) permanently discontinued treatment with tofacitinib, and 16 (7%) were either hospitalized or received intravenous antiviral drugs. The crude HZ IR across the development program was 4.4 per 100 patient-years (95% CI 3.8–4.9), but the IR was substantially higher within Asia (7.7 per 100 patient-years, 95% CI 6.4–9.3). Older age was associated with HZ (odds ratio 1.9, 95% CI 1.5–2.6), and IRs for HZ were similar between patients receiving 5 mg tofacitinib twice daily (4.4 per 100 patient-years, 95% CI 3.2–6.0) and those receiving 10 mg twice daily (4.2 per 100 patient-years, 95% CI 3.1–5.8). In the phase III trials among placebo recipients, the incidence of HZ was 1.5 per 100 patient-years (95% CI 0.5–4.6). Conclusion In the Tofacitinib RA Development Program, increased rates of HZ were observed in patients treated with tofacitinib compared with those receiving placebo, particularly among patients within Asia. Complicated HZ among tofacitinib-treated patients was rare. PMID:24943354

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

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.

The GKSS beamlines at PETRA III and DORIS III

NASA Astrophysics Data System (ADS)

Haibel, A.; Beckmann, F.; Dose, T.; Herzen, J.; Utcke, S.; Lippmann, T.; Schell, N.; Schreyer, A.

2008-08-01

Due to the high brilliance of the new storage ring PETRA III at DESY in Hamburg, the low emittance of 1 nmrad and the high fraction of coherent photons also in the hard X-ray range extremely intense and sharply focused X-ray light will be provided. These advantages of the beam fulfill excellently the qualifications for the planned Imaging BeamLine IBL and the High Energy Materials Science Beamline (HEMS) at PETRA III, i.e. for absorption tomography, phase enhanced and phase contrast experiments, for diffraction, for nano focusing, for nano tomography, and for high speed or in-situ experiments with highest spatial resolution. The existing HARWI II beamline at the DORIS III storage ring at DESY completes the GKSS beamline concept with setups for high energy tomography (16-150 keV) and diffraction (16-250 keV), characterized by a large field of view and an excellent absorption contrast with spatial resolutions down to 2 μm.

General Improvement of Reading Instruction, Grades 1-12, Teacher Training Program of Title III, P.L. 89-10. Evaluation of Second Phase of Program, Summer 1968.

ERIC Educational Resources Information Center

Brookland-Cayce Schools, West Columbia, SC.

An evaluation of the second phase of a projected 3-year Title III inservice reading instruction program for teaching personnel is presented after one and one-half years of operation in 16 Cayce-West Columbia, South Carolina, schools. Included is an evaluation prepared by each of the 11 elementary supervisors which includes objectives and how they…

Installation Restoration Program Records Search for Westover Air Force Base, Massachusetts.

DTIC Science & Technology

1982-04-01

Phase III (not part of this contract) consists of a technology base development study to support the development of project plans for controlling...determine the extent and magnitude of the contaminant migration. Phase III (not part of this contract) consists of a technology base development study to...number of vegetation studies have attempted to classify the potential climax vegetation within the region of Westover AFB (Braun, 1972; Kuchler, 1975

OPTIM trial: a Phase III trial of an oncolytic herpes virus encoding GM-CSF for unresectable stage III or IV melanoma.

PubMed

Kaufman, Howard L; Bines, Steven D

2010-06-01

There are few effective treatment options available for patients with advanced melanoma. An oncolytic herpes simplex virus type 1 encoding granulocyte macrophage colony-stimulating factor (GM-CSF; Oncovex(GM-CSF)) for direct injection into accessible melanoma lesions resulted in a 28% objective response rate in a Phase II clinical trial. Responding patients demonstrated regression of both injected and noninjected lesions highlighting the dual mechanism of action of Oncovex(GM-CSF) that includes both a direct oncolytic effect in injected tumors and a secondary immune-mediated anti-tumor effect on noninjected tumors. Based on these preliminary results a prospective, randomized Phase III clinical trial in patients with unresectable Stage IIIb or c and Stage IV melanoma has been initiated. The rationale, study design, end points and future development of the Oncovex(GM-CSF) Pivotal Trial in Melanoma (OPTIM) trial are discussed in this article.

Growth and characterization of single crystal rocksalt LaAs using LuAs barrier layers

NASA Astrophysics Data System (ADS)

Krivoy, E. M.; Rahimi, S.; Nair, H. P.; Salas, R.; Maddox, S. J.; Ironside, D. J.; Jiang, Y.; Dasika, V. D.; Ferrer, D. A.; Kelp, G.; Shvets, G.; Akinwande, D.; Bank, S. R.

2012-11-01

We demonstrate the growth of high-quality, single crystal, rocksalt LaAs on III-V substrates; employing thin well-behaved LuAs barriers layers at the III-V/LaAs interfaces to suppress nucleation of other LaAs phases, interfacial reactions between GaAs and LaAs, and polycrystalline LaAs growth. This method enables growth of single crystal epitaxial rocksalt LaAs with enhanced structural and electrical properties. Temperature-dependent resistivity and optical reflectivity measurements suggest that epitaxial LaAs is semimetallic, consistent with bandstructure calculations in literature. LaAs exhibits distinct electrical and optical properties, as compared with previously reported rare-earth arsenide materials, with a room-temperature resistivity of ˜459 μΩ-cm and an optical transmission window >50% between ˜3-5 μm.

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.

Safety data from the phase III Japanese ACHIEVE trial: part of an international, prospective, planned pooled analysis of six phase III trials comparing 3 versus 6 months of oxaliplatin-based adjuvant chemotherapy for stage III colon cancer.

PubMed

Kotaka, Masahito; Yamanaka, Takeharu; Yoshino, Takayuki; Manaka, Dai; Eto, Tetsuya; Hasegawa, Junichi; Takagane, Akinori; Nakamura, Masato; Kato, Takeshi; Munemoto, Yoshinori; Nakamura, Fumitaka; Bando, Hiroyuki; Taniguchi, Hiroki; Gamoh, Makio; Shiozawa, Manabu; Saji, Shigetoyo; Maehara, Yoshihiko; Mizushima, Tsunekazu; Ohtsu, Atsushi; Mori, Masaki

2018-01-01

The International Duration Evaluation of Adjuvant chemotherapy project investigated whether a shorter duration of oxaliplatin-based adjuvant chemotherapy was as effective as 6 months of identical chemotherapy for resected stage III colon cancer. As part of this project, we report safety data from the Japanese ACHIEVE study (JFMC47-1202-C3). ACHIEVE was an open-label, multicentre trial randomising patients with stage III colon cancer to receive 3 m or 6 m of mFOLFOX6/CAPOX after surgery. Choice of regimen was declared before randomisation by a site investigator. Between August 2012 and June 2014, 1313 patients were enrolled and, of those, 1277 were analysed for the safety analysis, with 635 in arm 6 (mFOLFOX6, n=158; CAPOX, n=477) and 642 in arm 3 (mFOLFOX6, n=161; CAPOX, n=481). Grade 3 or worse peripheral sensory neuropathy (PSN) developed in 5%/0.6% of patients receiving mFOLFOX6 in arm 6/3 (p=0.019) and 6%/1% of those receiving CAPOX in arm 6/3 (p<0.001). Similarly, grade 2 or worse PSN developed in 36%/11% of patients receiving mFOLFOX6 in arm 6/3 (p<0.001) and 37%/14% of those receiving CAPOX in arm 6/3 (p<0.001). An association between baseline creatinine clearance (CCr) and adverse events (AEs) was found that patients with CAPOX were significantly more likely to develop AEs ≥grade 3 when they had a CCr ≤50 (OR 1.67; p=0.048). We confirmed in the Japanese population that the shorter duration of adjuvant chemotherapy resulted in a significant reduction of PSN. In patients with CAPOX, renal function was significantly related to severe AEs. UMIN000008543, Results.

Safety data from the phase III Japanese ACHIEVE trial: part of an international, prospective, planned pooled analysis of six phase III trials comparing 3 versus 6 months of oxaliplatin-based adjuvant chemotherapy for stage III colon cancer

PubMed Central

Kotaka, Masahito; Yamanaka, Takeharu; Yoshino, Takayuki; Manaka, Dai; Eto, Tetsuya; Hasegawa, Junichi; Takagane, Akinori; Nakamura, Masato; Kato, Takeshi; Munemoto, Yoshinori; Nakamura, Fumitaka; Bando, Hiroyuki; Taniguchi, Hiroki; Gamoh, Makio; Shiozawa, Manabu; Saji, Shigetoyo; Maehara, Yoshihiko; Mizushima, Tsunekazu; Ohtsu, Atsushi; Mori, Masaki

2018-01-01

Background The International Duration Evaluation of Adjuvant chemotherapy project investigated whether a shorter duration of oxaliplatin-based adjuvant chemotherapy was as effective as 6 months of identical chemotherapy for resected stage III colon cancer. As part of this project, we report safety data from the Japanese ACHIEVE study (JFMC47-1202-C3). Patients and methods ACHIEVE was an open-label, multicentre trial randomising patients with stage III colon cancer to receive 3 m or 6 m of mFOLFOX6/CAPOX after surgery. Choice of regimen was declared before randomisation by a site investigator. Results Between August 2012 and June 2014, 1313 patients were enrolled and, of those, 1277 were analysed for the safety analysis, with 635 in arm 6 (mFOLFOX6, n=158; CAPOX, n=477) and 642 in arm 3 (mFOLFOX6, n=161; CAPOX, n=481). Grade 3 or worse peripheral sensory neuropathy (PSN) developed in 5%/0.6% of patients receiving mFOLFOX6 in arm 6/3 (p=0.019) and 6%/1% of those receiving CAPOX in arm 6/3 (p<0.001). Similarly, grade 2 or worse PSN developed in 36%/11% of patients receiving mFOLFOX6 in arm 6/3 (p<0.001) and 37%/14% of those receiving CAPOX in arm 6/3 (p<0.001). An association between baseline creatinine clearance (CCr) and adverse events (AEs) was found that patients with CAPOX were significantly more likely to develop AEs ≥grade 3 when they had a CCr ≤50 (OR 1.67; p=0.048). Conclusions We confirmed in the Japanese population that the shorter duration of adjuvant chemotherapy resulted in a significant reduction of PSN. In patients with CAPOX, renal function was significantly related to severe AEs. Trial registration number UMIN000008543, Results. PMID:29713499

Effect of scaling and root planing on gingival crevicular fluid level of YKL-40 acute phase protein in chronic periodontitis patients with or without type 2 diabetes mellitus: A clinico-biochemical study

PubMed Central

Damodar, Sini; Mehta, Dhoom Singh

2018-01-01

Background: The aim of the present study was to evaluate the gingival crevicular fluid (GCF) levels of YKL-40 acute phase protein in chronic periodontitis (CP) with and without type 2 diabetes and also to assess the effect of periodontal therapy (scaling and root planing [SRP]) on this GCF biomarker and the clinical parameters. YKL-40 is derived from tyrosine (Y), lysine (K), and leucine (L) with a molecular weight of 40 kDa. Materials and Methods: A total of 105 individuals (30–60 years) were grouped as 35 individuals each in three groups (Group I – healthy; Group II – CP with diabetes mellitus [DM]; and Group III – CP). Clinical parameters including plaque index, gingival index, probing pocket depth, and clinical attachment level followed by GCF sample collection from test sites were done at baseline and 6 weeks after SRP (among Group II and Group III patients). GCF YKL-40 level was determined by enzyme-linked immunosorbent assay. Results: The mean GCF YKL-40 level at baseline was significantly lower for Group I (309.81 ± 124.93 pg/ml) as compared to Group II (924.88 ± 415.28 pg/ml) and Group III (834.08 ± 270.42 pg/ml), respectively (P < 0.001). The level reduced significantly 6 weeks after SRP for Group II (507.6 ± 265.03 pg/ml) and Group III (499.54 ± 293.38 pg/ml) (P < 0.001). Conclusion: The level of GCF YKL-40 in CP patients with or without DM is higher than healthy individuals and the level reduced 6 weeks post-SRP among Group II and Group III. Hence, YKL-40 can be considered as an important biomarker in the diagnosis of CP. PMID:29568171

Refinement of the Montreal Instrument for Cat Arthritis Testing, for Use by Veterinarians: detection of naturally occurring osteoarthritis in laboratory cats.

PubMed

Klinck, Mary P; Monteiro, Beatriz P; Lussier, Bertrand; Guillot, Martin; Moreau, Maxim; Otis, Colombe; Steagall, Paulo Vm; Frank, Diane; Martel-Pelletier, Johanne; Pelletier, Jean-Pierre; Del Castillo, Jérôme Re; Troncy, Eric

2017-09-01

Objectives Feline osteoarthritis causes pain and disability. Detection and measurement is challenging, relying heavily on owner report. This study describes refinement of the Montreal Instrument for Cat Arthritis Testing, for Use by Veterinarians. Methods A video analysis of osteoarthritic (n = 6) and non-osteoarthritic (n = 4) cats facilitated expansion of scale items. Three successive therapeutic trials (using gabapentin, tramadol and oral transmucosal meloxicam spray) in laboratory cats with and without natural osteoarthritis (n = 12-20), permitted construct validation (assessments of disease status sensitivity and therapeutic responsiveness) and further scale refinements based on performance. Results Scale osteoarthritic sensitivity improved from phase I to phase III; phase III scale total score ( P = 0.0001) and 4/5 subcategories - body posture ( P = 0.0006), gait ( P = 0.0031), jumping (0.0824) and global distance examination ( P = 0.0001) - detected osteoarthritic cats. Total score inter-rater (intra-class correlation coefficients [ICC] = 0.64-0.75), intra-rater (ICC = 0.90-0.91) and overall internal consistency (Cronbach's alpha = 0.85) reliability were good to excellent. von Frey anesthesiometer-induced paw withdrawal threshold increased with gabapentin in phase I, in osteoarthritic cats ( P <0.001) but not in non-osteoarthritic cats ( P = 0.075). Night-time activity increased during gabapentin treatment. Objective measures also detected tramadol and/or meloxicam treatment effects in osteoarthritic cats in phases II and III. There was some treatment responsiveness: in phase I, 3/10 subcategory scores improved ( P <0.09) in treated osteoarthritic cats; in phase II, 3/8 subcategories; and in phase III, 1/5 subcategories improved ( P <0.096). Conclusions and relevance The revised scale detected naturally occurring osteoarthritis, but not treatment effects, in laboratory cats, suggesting future potential for screening of at-risk cats. Further study is needed to confirm reliability, validity (disease sensitivity and treatment responsiveness) and clinical feasibility, as well as cut-off scores for osteoarthritic vs non-osteoarthritic status, in client-owned cats.

A crossover study of the combination therapy of metformin and exenatide or biphasic insulin aspart 30 in overweight or obese patients newly diagnosed with type 2 diabetes mellitus

PubMed Central

Quan, Huibiao; Zhang, Huachuan; Wei, Weiping; Fang, Tuanyu; Chen, Daoxiong; Chen, Kaining

2017-01-01

The aim of the present study was to explore the effects of various combinations of exenatide, metformin (MET) and biphasic insulin aspart 30 (BIA30) on type 2 diabetes mellitus (T2DM). Two hundred overweight or obese patients newly diagnosed with T2DM were evenly randomized into two groups: A (twice daily for all: Phase I, 5 µg exenatide + 0.5 g MET for 4 weeks, then 10 µg exenatide + 0.5 g MET for 8 weeks; Phase II, 0.5 g MET for 12 weeks; Phase III, 0.3–0.4 U/kg/day BIA30 + 0.5 g MET for 12 weeks) and B (Phases I, II, III matched the phases III, II and I in group A). In groups A and B a significant decrease and increase, respectively, in glycated hemoglobin (HbAlc) and body mass index (BMI) was noted during Phase I. A 3.2±0.4-kg decrease in body weight in group A and a 2.6±0.3-kg increase in group B was observed. In Phase II, HbAlc was significantly increased in both groups (P<0.05). In Phase III, the BMI was increased in group A and reduced in group B (P<0.05). There was a 3.8±0.4-kg weight decrease in group B and 4.2±0.5-kg increase in group A (P<0.05). The combination of exenatide and MET promoted weight loss, glycemic control, β-cell function index, C peptide and adiponectin levels. These results suggested that the combination of exenatide and MET is better than the combination of BIA and MET for the therapy of overweight or obese patients newly diagnosed with T2DM. PMID:28912879

Guideline-based intervention to reduce telemetry rates in a large tertiary centre.

PubMed

Ramkumar, Satish; Tsoi, Edward H; Raghunath, Ajay; Dias, Floyd F; Li Wai Suen, Christopher; Tsoi, Andrew H; Mansfield, Darren R

2017-07-01

Inappropriate cardiac telemetry use is associated with reduced patient flow and increased healthcare costs. To evaluate the outcomes of guideline-based application of cardiac telemetry. Phase I involved a prospective audit (March to August 2011) of telemetry use at a tertiary hospital. Data were collected on indication for telemetry and clinical outcomes. Phase II prospectively included patients more than 18 years under general medicine requiring ward-based telemetry. As phase II occurred at a time remotely from phase I, an audit similar to phase I (phase II - baseline) was completed prior to a 3-month intervention (May to August 2015). The intervention consisted of a daily telemetry ward round and an admission form based on the American Heart Association guidelines (class I, telemetry indicated; class II, telemetry maybe indicated; class III, telemetry not indicated). Patient demographics, telemetry data, and clinical outcomes were studied. Primary endpoint was the percentage reduction of class III indications, while secondary endpoint included telemetry duration. In phase I (n = 200), 38% were admitted with a class III indication resulting in no change in clinical management. A total of 74 patients was included in phase II baseline (mean ± standard deviation (SD) age 73 years ± 14.9, 57% male), whilst 65 patients were included in the intervention (mean ± SD age 71 years ± 18.4, 35% male). Both groups had similar baseline characteristics. There was a reduction in class III admissions post-intervention from 38% to 11%, P < 0.001. Intervention was associated with a reduction in median telemetry duration (1.8 ± 1.8 vs 2.4 ± 2.5 days, P = 0.047); however, length of stay was similar in both groups (P > 0.05). Guideline-based telemetry admissions and a regular telemetry ward round are associated with a reduction in inappropriate telemetry use. © 2017 Royal Australasian College of Physicians.

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

Optimization of vehicle deceleration to reduce occupant injury risks in frontal impact.

PubMed

Mizuno, Koji; Itakura, Takuya; Hirabayashi, Satoko; Tanaka, Eiichi; Ito, Daisuke

2014-01-01

In vehicle frontal impacts, vehicle acceleration has a large effect on occupant loadings and injury risks. In this research, an optimal vehicle crash pulse was determined systematically to reduce injury measures of rear seat occupants by using mathematical simulations. The vehicle crash pulse was optimized based on a vehicle deceleration-deformation diagram under the conditions that the initial velocity and the maximum vehicle deformation were constant. Initially, a spring-mass model was used to understand the fundamental parameters for optimization. In order to investigate the optimization under a more realistic situation, the vehicle crash pulse was also optimized using a multibody model of a Hybrid III dummy seated in the rear seat for the objective functions of chest acceleration and chest deflection. A sled test using a Hybrid III dummy was carried out to confirm the simulation results. Finally, the optimal crash pulses determined from the multibody simulation were applied to a human finite element (FE) model. The optimized crash pulse to minimize the occupant deceleration had a concave shape: a high deceleration in the initial phase, low in the middle phase, and high again in the final phase. This crash pulse shape depended on the occupant restraint stiffness. The optimized crash pulse determined from the multibody simulation was comparable to that from the spring-mass model. From the sled test, it was demonstrated that the optimized crash pulse was effective for the reduction of chest acceleration. The crash pulse was also optimized for the objective function of chest deflection. The optimized crash pulse in the final phase was lower than that obtained for the minimization of chest acceleration. In the FE analysis of the human FE model, the optimized pulse for the objective function of the Hybrid III chest deflection was effective in reducing rib fracture risks. The optimized crash pulse has a concave shape and is dependent on the occupant restraint stiffness and maximum vehicle deformation. The shapes of the optimized crash pulse in the final phase were different for the objective functions of chest acceleration and chest deflection due to the inertial forces of the head and upper extremities. From the human FE model analysis it was found that the optimized crash pulse for the Hybrid III chest deflection can substantially reduce the risk of rib cage fractures. Supplemental materials are available for this article. Go to the publisher's online edition of Traffic Injury Prevention to view the supplemental file.

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

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.

Pharmacotherapies for Obesity: Past, Current, and Future Therapies

PubMed Central

Ioannides-Demos, Lisa L.; Piccenna, Loretta; McNeil, John J.

2011-01-01

Past therapies for the treatment of obesity have typically involved pharmacological agents usually in combination with a calorie-controlled diet. This paper reviews the efficacy and safety of pharmacotherapies for obesity focusing on drugs approved for long-term therapy (orlistat), drugs approved for short-term use (amfepramone [diethylpropion], phentermine), recently withdrawn therapies (rimonabant, sibutamine) and drugs evaluated in Phase III studies (taranabant, pramlintide, lorcaserin and tesofensine and combination therapies of topiramate plus phentermine, bupropion plus naltrexone, and bupropion plus zonisamide). No current pharmacotherapy possesses the efficacy needed to produce substantial weight loss in morbidly obese patients. Meta-analyses support a significant though modest loss in bodyweight with a mean weight difference of 4.7 kg (95% CI 4.1 to 5.3 kg) for rimonabant, 4.2 kg (95% CI 3.6 to 4.8 kg) for sibutramine and 2.9 kg (95% CI 2.5 to 3.2 kg) for orlistat compared to placebo at ≥12 months. Of the Phase III pharmacotherapies, lorcaserin, taranabant, topiramate and bupropion with naltrexone have demonstrated significant weight loss compared to placebo at ≥12 months. Some pharmacotherapies have also demonstrated clinical benefits. Further studies are required in some populations such as younger and older people whilst the long term safety continues to be a major consideration and has led to the withdrawal of several drugs. PMID:21197148

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.

Cost-effectiveness analysis of apatinib treatment for chemotherapy-refractory advanced gastric cancer.

PubMed

Chen, Hong-Dou; Zhou, Jing; Wen, Feng; Zhang, Peng-Fei; Zhou, Ke-Xun; Zheng, Han-Rui; Yang, Yu; Li, Qiu

2017-02-01

Apatinib, a third-line or later treatment for advanced gastric cancer (aGC), was shown to improve overall survival and progression-free survival (PFS) compared with placebo in the phase III trial. Given the modest benefit with high costs, we further evaluated the cost-effectiveness of apatinib for patients with chemotherapy-refractory aGC. A Markov model was developed to simulate the disease process of aGC (PFS, progressive disease, and death) and estimate the incremental cost-effectiveness ratio (ICER) of apatinib to placebo. The health outcomes and utility scores were derived from the phase III trial and previously published sources, respectively. Total costs were calculated from the perspective of the Chinese health-care payer. Sensitivity analysis was used to explore model uncertainties. Treatment with apatinib was estimated to provide an incremental 0.09 quality-adjusted life years (QALYs) at an incremental cost of $8113.86 compared with placebo, which resulted in an ICER of $90,154.00 per QALY. Sensitivity analysis showed that across the wide variation of parameters, the ICER exceeded the willingness-to-pay threshold of $23,700.00 per QALY which was three times the Gross Domestic Product per Capita in China. Apatinib is not a cost-effective option for patients with aGC who experienced failure of at least two lines chemotherapy in China. However, for its positive clinical value and subliminal demand, apatinib can provide a new therapeutic option.

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.

Accelerated re-epithelialization of partial-thickness skin wounds by a topical betulin gel: Results of a randomized phase III clinical trials program.

PubMed

Barret, Juan P; Podmelle, Fred; Lipový, Břetislav; Rennekampff, Hans-Oliver; Schumann, Hauke; Schwieger-Briel, Agnes; Zahn, Tobias R; Metelmann, Hans-Robert

2017-09-01

The clinical significance of timely re-epithelialization is obvious in burn care, since delayed wound closure is enhancing the risk of wound site infection and extensive scarring. Topical treatments that accelerate wound healing are urgently needed to reduce these sequelae. Evidence from preliminary studies suggests that betulin can accelerate the healing of different types of wounds, including second degree burns and split-thickness skin graft wounds. The goal of this combined study program consisting of two randomized phase III clinical trials in parallel is to evaluate whether a topical betulin gel (TBG) is accelerating re-epithelialization of split-thickness skin graft (STSG) donor site wounds compared to standard of care. Two parallel blindly evaluated, randomised, controlled, multicentre phase III clinical trials were performed in adults undergoing STSG surgery (EudraCT nos. 2012-003390-26 and 2012-000777-23). Donor site wounds were split into two equal halves and randomized 1:1 to standard of care (a non-adhesive moist wound dressing) or standard of care plus TBG consisting of 10% birch bark extract and 90% sunflower oil (Episalvan, Birken AG, Niefern-Oeschelbronn, Germany). The primary efficacy assessment was the intra-individual difference in time to wound closure assessed from digital photographs by three blinded experts. A total of 219 patients were included and treated in the two trials. Wounds closed faster with TBG than without it (15.3 vs. 16.5 days; mean intra-individual difference=-1.1 days [95% CI, -1.5 to -0.7]; p<0.0001). This agreed with unblinded direct clinical assessment (difference=-2.1 days [95% CI, -2.7 to -1.5]; p<0.0001). Adverse events possibly related to treatment were mild or moderate and mostly at the application site. TBG accelerates re-epithelialization of partial thickness wounds compared to the current standard of care, providing a well-tolerated contribution to burn care in practice. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

Safety and immunogenicity of a tetravalent dengue vaccine in healthy children aged 2-11 years in Malaysia: a randomized, placebo-controlled, Phase III study.

PubMed

Hss, Amar-Singh; Koh, Mia-Tuang; Tan, Kah Kee; Chan, Lee Gaik; Zhou, Lynn; Bouckenooghe, Alain; Crevat, Denis; Hutagalung, Yanee

2013-12-02

Dengue disease is a major public health problem across the Asia-Pacific region for which there is no licensed vaccine or treatment. We evaluated the safety and immunogenicity of Phase III lots of a candidate vaccine (CYD-TDV) in children in Malaysia. In this observer-blind, placebo-controlled, Phase III study, children aged 2-11 years were randomized (4:1) to receive CYD-TDV or placebo at 0, 6 and 12 months. Primary endpoints included assessment of reactogenicity following each dose, adverse events (AEs) and serious AEs (SAEs) reported throughout the study, and immunogenicity expressed as geometric mean titres (GMTs) and distribution of dengue virus (DENV) neutralizing antibody titres. 250 participants enrolled in the study (CYD-TDV: n=199; placebo: n=51). There was a trend for reactogenicity to be higher with CYD-TDV than with placebo post-dose 1 (75.4% versus 68.6%) and post-dose 2 (71.6% versus 62.0%) and slightly lower post-dose 3 (57.9% versus 64.0%). Unsolicited AEs declined in frequency with each subsequent dose and were similar overall between groups (CYD-TDV: 53.8%; placebo: 49.0%). Most AEs were of Grade 1 intensity and were transient. SAEs were reported by 5.5% and 11.8% of participants in the CYD-TDV and placebo groups, respectively. No deaths were reported. Baseline seropositivity against each of the four DENV serotypes was similar between groups, ranging from 24.0% (DENV-4) to 36.7% (DENV-3). In the CYD-TDV group, GMTs increased post-dose 2 for all serotypes compared with baseline, ranging from 4.8 (DENV-1) to 8.1-fold (DENV-3). GMTs further increased post-dose 3 for DENV-1 and DENV-2. Compared with baseline, individual titre increases ranged from 6.1-fold (DENV-1) to 7.96-fold (DENV-3). This study demonstrated a satisfactory safety profile and a balanced humoral immune response against all four DENV serotypes for CYD-TDV administered via a three-dose regimen to children in Malaysia. Copyright © 2013 The Authors. Published by Elsevier Ltd.. All rights reserved.

Method for Improving Mg Doping During Group-III Nitride MOCVD

DOEpatents

Creighton, J. Randall; Wang, George T.

2008-11-11

A method for improving Mg doping of Group III-N materials grown by MOCVD preventing condensation in the gas phase or on reactor surfaces of adducts of magnesocene and ammonia by suitably heating reactor surfaces between the location of mixing of the magnesocene and ammonia reactants and the Group III-nitride surface whereon growth is to occur.

Impact of Availability of Companion Diagnostics on the Clinical Development of Anticancer Drugs.

PubMed

Tibau, Ariadna; Díez-González, Laura; Navarro, Beatriz; Galán-Moya, Eva M; Templeton, Arnoud J; Seruga, Bostjan; Pandiella, Atanasio; Amir, Eitan; Ocana, Alberto

2017-06-01

Companion diagnostics permit the selection of patients likely to respond to targeted anticancer drugs; however, it is unclear if the drug development process differs between drugs developed with or without companion diagnostics. Identification of differences in study design could help future clinical development. Anticancer drugs approved for use in solid tumors between 28 September 2000 and 4 January 2014 were identified using a search of the US FDA website. Phase III trials supporting registration were extracted from the drug label. Each published study was reviewed to obtain information about the phase I and II trials used for the development of the respective drug. We identified 35 drugs and 59 phase III randomized trials supporting regulatory approval. Fifty-three phase I trials and 47 phase II trials were cited in the studies and were used to support the design of these phase III trials. The approval of drugs using a companion diagnostic has increased over time (p for trend 0.01). Expansion cohorts were more frequently observed with drugs developed with a companion diagnostic (62 vs. 20%; p = 0.005). No differences between drugs developed with or without a companion diagnostic were observed for the design of phase I and II studies. The approval of drugs developed with a companion diagnostic has increased over time. The availability of a companion diagnostic was associated with more frequent use of phase I expansion cohorts comprising patients selected by the companion diagnostic.

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

NASA Astrophysics Data System (ADS)

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

2003-10-01

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

Preclinical characterization of anticancer gallium(III) complexes: solubility, stability, lipophilicity and binding to serum proteins.

PubMed

Rudnev, Alexander V; Foteeva, Lidia S; Kowol, Christian; Berger, Roland; Jakupec, Michael A; Arion, Vladimir B; Timerbaev, Andrei R; Keppler, Bernhard K

2006-11-01

The discovery and development of gallium(III) complexes capable of inhibiting tumor growth is an emerging area of anticancer drug research. A range of novel gallium coordination compounds with established cytotoxic efficacy have been characterized in terms of desirable chemical and biochemical properties and compared with tris(8-quinolinolato)gallium(III) (KP46), a lead anticancer gallium-based candidate that successfully finished phase I clinical trials (under the name FFC11), showing activity against renal cell cancer. In view of probable oral administration, drug-like parameters, such as solubility in water, saline and 0.5% dimethyl sulfoxide, stability against hydrolysis, measured as the rate constant of hydrolytic degradation in water or physiological buffer using a capillary zone electrophoresis (CZE) assay, and the octanol-water partition coefficient (logP) providing a rational estimate of a drug's lipophilicity, have been evaluated and compared. The differences in bioavailability characteristics between different complexes were discussed within the formalism of structure-activity relationships. The reactivity toward major serum transport proteins, albumin and transferrin, was also assayed in order to elucidate the drug's distribution pathway after intestinal absorption. According to the values of apparent binding rate constants determined by CZE, both KP46 and bis(2-acetylpyridine-4,4-dimethyl-3-thiosemicarbazonato-N,N,S)gallium(III) tetrachlorogallate(III) (KP1089) bind to transferrin faster than to albumin. This implies that transferrin would rather mediate the accumulation of gallium antineoplastic agents in solid tumors. A tendency of being faster converted into the protein-bound form found for KP1089 (due possibly to non-covalent binding) seems complementary to its greater in vitro antiproliferative activity.

Etoposide and cisplatin versus paclitaxel and carboplatin with concurrent thoracic radiotherapy in unresectable stage III non-small cell lung cancer: a multicenter randomized phase III trial.

PubMed

Liang, J; Bi, N; Wu, S; Chen, M; Lv, C; Zhao, L; Shi, A; Jiang, W; Xu, Y; Zhou, Z; Wang, W; Chen, D; Hui, Z; Lv, J; Zhang, H; Feng, Q; Xiao, Z; Wang, X; Liu, L; Zhang, T; Du, L; Chen, W; Shyr, Y; Yin, W; Li, J; He, J; Wang, L

2017-04-01

The optimal chemotherapy regimen administered currently with radiation in patients with stage III non-small cell lung cancer (NSCLC) remains unclear. A multicenter phase III trial was conducted to compare the efficacy of concurrent thoracic radiation therapy with either etoposide/cisplatin (EP) or carboplatin/paclitaxel (PC) in patients with stage III NSCLC. Patients were randomly received 60-66 Gy of thoracic radiation therapy concurrent with either etoposide 50 mg/m2 on days 1-5 and cisplatin 50 mg/m2 on days 1 and 8 every 4 weeks for two cycles (EP arm), or paclitaxel 45 mg/m2 and carboplatin (AUC 2) on day 1 weekly (PC arm). The primary end point was overall survival (OS). The study was designed with 80% power to detect a 17% superiority in 3-year OS with a type I error rate of 0.05. A total of 200 patients were randomized and 191 patients were treated (95 in the EP arm and 96 in the PC arm). With a median follow-up time of 73 months, the 3-year OS was significantly higher in the EP arm than that of the PC arm. The estimated difference was 15.0% (95% CI 2.0%-28.0%) and P value of 0.024. Median survival times were 23.3 months in the EP arm and 20.7 months in the PC arm (log-rank test P = 0.095, HR 0.76, 95%CI 0.55-1.05). The incidence of Grade ≥2 radiation pneumonitis was higher in the PC arm (33.3% versus 18.9%, P = 0.036), while the incidence of Grade ≥3 esophagitis was higher in the EP arm (20.0% versus 6.3%, P = 0.009). EP might be superior to weekly PC in terms of OS in the setting of concurrent chemoradiation for unresectable stage III NSCLC. NCT01494558. © 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.

Plasma homovanillic acid in the prodromal phase of schizophrenia.

PubMed

Sumiyoshi, T; Kurachi, M; Kurokawa, K; Yotsutsuji, T; Uehara, T; Itoh, H; Saitoh, O

2000-03-01

Plasma levels of homovanillic acid (pHVA) have been used as a peripheral measure of central dopaminergic activity. Despite a large body of studies investigating pHVA in schizophrenia, little is known about pHVA in patients in the prodromal phase of the illness. Plasma HVA levels of 12 male outpatients meeting DSM-III-R criteria for the prodromal phase of schizophrenia at the time of blood sampling (who later developed psychotic symptoms) were compared with those of 12 normal male healthy volunteers. Task amounts in the Kraepelin arithmetic test at the time of blood sampling were compared between the prodromal patients and normal controls and were correlated with pHVA levels. The prodromal patients had significantly higher pHVA levels compared with normal control subjects. The mean amount of the arithmetic task for the prodromal patients was significantly less than that for controls. In the patient group, a significant negative correlation was observed between pHVA levels and the task amounts. Data from the present study indicate the presence of dopaminergic dysfunction in the prodromal stage of schizophrenia that is associated with neuropsychological impairment. Increased pHVA levels in the prodromal patients may have implications for early detection of schizophrenia.

Electrophysiological evidence during episodic prospection implicates medial prefrontal and bilateral middle temporal gyrus.

PubMed

Hsu, Chia-Fen; Sonuga-Barke, Edmund J S

2016-08-01

fMRI studies have implicated the medial prefrontal cortex and medial temporal lobe, components of the default mode network (DMN), in episodic prospection. This study compared quantitative EEG localized to these DMN regions during prospection and during resting and while waiting for rewards. EEG was recorded in twenty-two adults while they were asked to (i) envision future monetary episodes; (ii) wait for rewards and (iii) rest. Activation sources were localized to core DMN regions. EEG power and phase coherence were compared across conditions. Prospection, compared to resting and waiting, was associated with reduced power in the medial prefrontal gyrus and increased power in the bilateral medial temporal gyrus across frequency bands as well as greater phase synchrony between these regions in the delta band. The current quantitative EEG analysis confirms prior fMRI research suggesting that medial prefrontal and medial temporal gyrus interactions are central to the capacity for episodic prospection. Copyright © 2016 Elsevier B.V. All rights reserved.

Sorption of Ferrioxime B to Synthetic and Biogenic layer type Mn Oxides

NASA Astrophysics Data System (ADS)

Duckworth, O. W.; Bargar, J. R.; Sposito, G.

2005-12-01

Siderophores are biogenic chelating agents produced in terrestrial and marine environments to increase the bioavailablity of ferric iron. Recent work has suggested that both aqueous and solid-phase Mn(III) may affect siderophore-mediated iron transport, but no information appears to be available about the effect of solid-phase Mn(IV). To probe the effect of solid-phase Mn(IV), we studied the sorption reaction of ferrioxamine B [principally the species, Fe(III)HDFOB+, an Fe(III) chelate of the trihydroxamate siderophore, desferrioxamine B (DFOB)] with two synthetic birnessites [layer type Mn(IV) oxides] and a biogenic birnessite produced by Pseudomonas putida MnB1. We found that all of these predominantly Mn(IV) oxides greatly reduced the aqueous concentration of Fe(III)HDFOB+ over the pH range between 5 and 9. After 72 h equilibration time at pH 8, the sorption behavior for the synthetic birnessites could be accurately described by a Langmuir isotherm; for the biogenic oxide, a Freundlich isotherm was best utilized to model the sorption data. To study the molecular nature of the interaction between the Fe(III)HDFOB+ complex and the oxide surface, Fe K-edge extended X-Ray absorption fine structure (EXAFS) spectroscopy was employed. Analysis of the X-ray absorption spectra indicated that Fe(III) associated with the Mn(IV) oxides is not complexed with DFOB, but instead is incorporated into the mineral structure, thus implying that the Mn(IV) oxides displaced Fe(III) from the siderophore complex. These results indicate that manganese oxides, including biominerals, may strongly sequester iron from soluble ferric complexes and thus may play a significant role in the biogeochemical cycling of iron.

The Importance of pH, Oxygen, and Bitumen on the Oxidation and Precipitation of Fe(III)-(oxy)hydroxides during Hydraulic Fracturing of Oil/Gas Shales

NASA Astrophysics Data System (ADS)

Jew, A. D.; Dustin, M. K.; Harrison, A. L.; Joe-Wong, C. M.; Thomas, D.; Maher, K.; Brown, G. E.; Bargar, J.

2016-12-01

Due to the rapid growth of hydraulic fracturing in the United States, understanding the cause for the rapid production drop off of new wells over the initial months of production is paramount. One possibility for the production decrease is pore occlusion caused by the oxidation of Fe(II)-bearing phases resulting in Fe(III) precipitates. To understand the release and fate of Fe in the shale systems, we reacted synthesized fracture fluid at 80oC with shale from four different geological localities (Marcellus Fm., Barnett Fm., Eagle Ford Fm., and Green River Fm.). A variety of wet chemical and synchrotron-based techniques (XRF mapping and x-ray absorption spectroscopy) were used to understand Fe release and solid phase Fe speciation. Solution pH was found to be the greatest factor for Fe release. Carbonate-poor Barnett and Marcellus shale showed rapid Fe release into solution followed by a plateau or significant drop in Fe concentrations indicating mineral precipitation. Conversely, in high carbonate shales, Eagle Ford and Green River, no Fe was detected in solution indicating fast Fe oxidation and precipitation. For all shale samples, bulk Fe EXAFS data show that a significant amount of Fe in the shales is bound directly to organic carbon. Throughout the course of the experiments inorganic Fe(II) phases (primarily pyrite) reacted while Fe(II) bound to C showed no indication of reaction. On the micron scale, XRF mapping coupled with μ-XANES spectroscopy showed that at pH < 4.0, Fe(III) bearing phases precipitated as diffuse surface precipitates of ferrihydrite, goethite, and magnetite away from Fe(II) point sources. In near circum-neutral pH systems, Fe(III)-bearing phases (goethite and hematite) form large particles 10's of μm's in diameter near Fe(II) point sources. Idealized systems containing synthesized fracturing fluid, dissolved ferrous chloride, and bitumen showed that bitumen released during reaction with fracturing fluids is capable of oxidizing Fe(II) to Fe(III) at pH's 2.0 and 7.0. This indicates that bitumen can play a large role in Fe oxidation and speciation in the subsurface. This work shows that shale mineralogy has a significant impact on the morphology and phases of Fe(III) precipitates in the subsurface which in turn can significantly impact subsurface solution flow.

Photoluminescence studies on the complexation of Eu(III) and Tb(III) with acetohydroxamic acid (AHA) in nitrate medium

NASA Astrophysics Data System (ADS)

Pathak, P. N.; Mohapatra, M.; Godbole, S. V.

2013-11-01

UREX process has been proposed for selective extraction of U(VI) and Tc(VII) from nitric acid medium (∼1 M HNO3) using tri-n-butyl phosphate (TBP) as extractant and retaining Pu, Np and fission products in the aqueous phase. The feasibility of the use of luminescence spectroscopy as a technique to understand the complexation of trivalent f-elements cations viz. Eu(III) and Tb(III) with acetohydroxamic acid (AHA) in nitric acid medium has been examined. The luminescence lifetimes for the 1 × 10-3 M Eu(III) and AHA complex system decreased with increased AHA concentration from 116 ± 0.2 μs (no AHA) to 1.6 ± 0.1 μs (0.1 M AHA) which was attributed to dynamic quenching. The corrected fluorescence intensities were used to calculate the stability constant (log K) for the formation of 1:1 Eu3+-AHA complex as 1.42 ± 0.64 under the conditions of this study. By contrast, the Tb(III)-AHA system at pH 3 (HNO3) did not show any significant variation in the life times of the excited state (364 ± 9 μs) suggesting the absence of dynamic quenching. The spectral changes in Tb(III)-AHA system showed the formation of 1:1 complex (log K: 1.72 ± 0.21). These studies suggest that the extent of AHA complexation with the rare earth elements will be insignificant as compared to tetravalent metal ions Pu(IV) and Np(IV) under UREX process conditions.

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.

Arsenite and ferrous iron oxidation linked to chemolithotrophic denitrification for the immobilization of arsenic in anoxic environments

USGS Publications Warehouse

Sun, W.; Sierra-Alvarez, R.; Milner, L.; Oremland, R.; Field, J.A.

2009-01-01

The objective of this study was to explore a bioremediation strategy based on injecting NO3- to support the anoxic oxidation of ferrous iron (Fe(II)) and arsenite (As(III)) in the subsurface as a means to immobilize As in the form of arsenate (As(V)) adsorbed onto biogenic ferric (Fe(III)) (hydr)oxides. Continuous flows and filled columns were used to simulate a natural anaerobic groundwater and sediment system with co-occurring As(III) and Fe(II) in the presence (column SF1) or absence (column SF2) of nitrate, respectively. During operation for 250 days, the average influent arsenic concentration of 567 ??g L-1 was reduced to 10.6 (??9.6) ??g L-1 in the effluent of column SF1. The cumulative removal of Fe(II) and As(III) in SF1 was 6.5 to 10-fold higher than that in SF2. Extraction and measurement of the mass of iron and arsenic immobilized on the sand packing of the columns were close to the iron and arsenic removed from the aqueous phase during column operation. The dominant speciation of the immobilized iron and arsenic was Fe(III) and As(V) in SF1, compared with Fe(II) and As(III) in SF2. The speciation was confirmed by X-ray diffraction (XRD) and X-ray photoelectron spectroscopy (XPS). The results indicate that microbial oxidation of As(III) and Fe(II) linked to denitrification resulted in the enhanced immobilization of aqueous arsenic in anaerobic environments by forming Fe(III) (hydr)oxide coated sands with adsorbed As(V). ?? 2009 American Chemical Society.

School Emergencies--Preparation Not Panic.

ERIC Educational Resources Information Center

Sousa, Barbara

1982-01-01

A three-phase emergency recognition course was designed to train 26 faculty and staff members to recognize and respond to emergency school medical situations. Phase I included comprehensive first aid, cardiopulmonary resuscitation (CPR), and injections. Phase II dealt with recognition of medical emergencies, and Phase III recertified those who had…

Puzzling calcite-III dimorphism: crystallography, high-pressure behavior, and pathway of single-crystal transitions

NASA Astrophysics Data System (ADS)

Pippinger, T.; Miletich, R.; Merlini, M.; Lotti, P.; Schouwink, P.; Yagi, T.; Crichton, W. A.; Hanfland, M.

2015-01-01

High-pressure phase transformations between the polymorphic forms I, II, III, and IIIb of CaCO3 were investigated by analytical in situ high-pressure high-temperature experiments on oriented single-crystal samples. All experiments at non-ambient conditions were carried out by means of Raman scattering, X-ray, and synchrotron diffraction techniques using diamond-anvil cells in the pressure range up to 6.5 GPa. The composite-gasket resistive heating technique was applied for all high-pressure investigations at temperatures up to 550 K. High-pressure Raman spectra reveal distinguishable characteristic spectral differences located in the wave number range of external modes with the occurrence of band splitting and shoulders due to subtle symmetry changes. Constraints from in situ observations suggest a stability field of CaCO3-IIIb at relatively low temperatures adjacent to the calcite-II field. Isothermal compression of calcite provides the sequence from I to II, IIIb, and finally, III, with all transformations showing volume discontinuities. Re-transformation at decreasing pressure from III oversteps the stability field of IIIb and demonstrates the pathway of pressure changes to determine the transition sequence. Clausius-Clapeyron slopes of the phase boundary lines were determined as: Δ P/Δ T = -2.79 ± 0.28 × 10-3 GPa K-1 (I-II); +1.87 ± 0.31 × 10-3 GPa K-1 (II/III); +4.01 ± 0.5 × 10-3 GPa K-1 (II/IIIb); -33.9 ± 0.4 × 10-3 GPa K-1 (IIIb/III). The triple point between phases II, IIIb, and III was determined by intersection and is located at 2.01(7) GPa/338(5) K. The pathway of transition from I over II to IIIb can be interpreted by displacement with small shear involved (by 2.9° on I/II and by 8.2° on II/IIIb). The former triad of calcite-I corresponds to the [20-1] direction in the P21/ c unit cell of phase II and to [101] in the pseudomonoclinic C setting of phase IIIb. Crystal structure investigations of triclinic CaCO3-III at non-ambient pressure-temperature conditions confirm the reported structure, and the small changes associated with the variation in P and T explain the broad stability of this structure with respect to variations in P and T. PVT equation of state parameters was determined from experimental data points in the range of 2.20-6.50 GPa at 298-405 K providing = 87.5(5.1) GPa, ( δK T/ δT) P = -0.21(0.23) GPa K-1, α 0 = 0.8(21.4) × 10-5 K-1, and α 1 = 1.0(3.7) × 10-7 K-1 using a second-order Birch-Murnaghan equation of state formalism.

Joint Operations 2030 - Phase III Report: The JO 2030 Capability Set (Operations interarmees 2030 - Rapport Phase III: L’ensemble capacitaire JO 2030)

DTIC Science & Technology

2011-04-01

a ‘strategy as process’ manner to develop capabilities that are flexible, adaptable and robust. 3.4 Future structures The need for agile...to develop models of the future security environment 3.4.10 Planning Under Deep Uncertainty Future structures The need for agile, flexible and... Organisation NEC Network Enabled Capability NGO Non Government Organisation NII Networking and Information Infrastructure PVO Private Voluntary

Phase fluctuation spectra: New radio science information to become available in the DSN tracking system Mark III-77

NASA Technical Reports Server (NTRS)

Berman, A. L.

1977-01-01

An algorithm was developed for the continuous and automatic computation of Doppler noise concurrently at four sample rate intervals, evenly spanning three orders of magnitude. Average temporal Doppler phase fluctuation spectra will be routinely available in the DSN tracking system Mark III-77 and require little additional processing. The basic (noise) data will be extracted from the archival tracking data file (ATDF) of the tracking data management system.

Synthetic coprecipitates of exopolysaccharides and ferrihydrite. Part I: Characterization

NASA Astrophysics Data System (ADS)

Mikutta, Christian; Mikutta, Robert; Bonneville, Steeve; Wagner, Friedrich; Voegelin, Andreas; Christl, Iso; Kretzschmar, Ruben

2008-02-01

Iron(III) (hydr)oxides formed at extracellular biosurfaces or in the presence of exopolymeric substances of microbes and plants may significantly differ in their structural and physical properties from their inorganic counterparts. We synthesized ferrihydrite (Fh) in solutions containing acid polysaccharides [polygalacturonic acid (PGA), alginate, xanthan] and compared its properties with that of an abiotic reference by means of X-ray diffraction, transmission electron microscopy, gas adsorption (N 2, CO 2), X-ray absorption spectroscopy, 57Fe Mössbauer spectroscopy, and electrophoretic mobility measurements. The coprecipitates formed contained up to 37 wt% polymer. Two-line Fh was the dominant mineral phase in all precipitates. The efficacy of polymers to precipitate Fh at neutral pH was higher for polymers with more carboxyl C (PGA ˜ alginate > xanthan). Pure Fh had a specific surface area of 300 m 2/g; coprecipitation of Fh with polymers reduced the detectable mineral surface area by up to 87%. Likewise, mineral micro- (<2 nm) and mesoporosity (2-10 nm) decreased by up to 85% with respect to pure Fh, indicative of a strong aggregation of Fh particles by polymers in freeze-dried state. C-1s STXM images showed the embedding of Fh particles in polymer matrices on the micrometer scale. Iron EXAFS spectroscopy revealed no significant changes in the local coordination of Fe(III) between pure Fh and Fh contained in PGA coprecipitates. 57Fe Mössbauer spectra of coprecipitates confirmed Fh as dominant mineral phase with a slightly reduced particle size and crystallinity of coprecipitate-Fh compared to pure Fh and/or a limited magnetic super-exchange between Fh particles in the coprecipitates due to magnetic dilution by the polysaccharides. The pH iep of pure Fh in 0.01 M NaClO 4 was 7.1. In contrast, coprecipitates of PGA and alginate had a pH iep < 2. Considering the differences in specific surface area, porosity, and net charge between the coprecipitates and pure Fh, composites of exopolysaccharides and Fe(III) (hydr)oxides are expected to differ in their geochemical reactivity from pure Fe(III) (hydr)oxides, even if the minerals have a similar crystallinity.

Randomized multicentre pilot study of sacubitril/valsartan versus irbesartan in patients with chronic kidney disease: United Kingdom Heart and Renal Protection (HARP)- III-rationale, trial design and baseline data.

PubMed

2017-12-01

Patients with chronic kidney disease (CKD) are at risk of progression to end-stage renal disease and cardiovascular disease. Data from other populations and animal experiments suggest that neprilysin inhibition (which augments the natriuretic peptide system) may reduce these risks, but clinical trials among patients with CKD are required to test this hypothesis. UK Heart and Renal Protection III (HARP-III) is a multicentre, double-blind, randomized controlled trial comparing sacubitril/valsartan 97/103 mg two times daily (an angiotensin receptor-neprilysin inhibitor) with irbesartan 300 mg one time daily among 414 patients with CKD. Patients ≥18 years of age with an estimated glomerular filtration rate (eGFR) of ≥45 but <60 mL/min/1.73 m2 and urine albumin:creatinine ratio (uACR) >20 mg/mmol or eGFR ≥20 but <45 mL/min/1.73 m2 (regardless of uACR) were invited to be screened. Following a 4- to 7-week pre-randomization single-blind placebo run-in phase (during which any current renin-angiotensin system inhibitors were stopped), willing and eligible participants were randomly assigned either sacubitril/valsartan or irbesartan and followed-up for 12 months. The primary aim was to compare the effects of sacubitril/valsartan and irbesartan on measured GFR after 12 months of therapy. Important secondary outcomes include effects on albuminuria, change in eGFR over time and the safety and tolerability of sacubitril/valsartan in CKD. Between November 2014 and January 2016, 620 patients attended a screening visit and 566 (91%) entered the pre-randomization run-in phase. Of these, 414 (73%) participants were randomized (mean age 63 years; 72% male). The mean eGFR was 34.0 mL/min/1.73 m2 and the median uACR was 58.5 mg/mmol. UK HARP-III will provide important information on the short-term effects of sacubitril/valsartan on renal function, tolerability and safety among patients with CKD. © The Author 2016. Published by Oxford University Press on behalf of ERA-EDTA.

Phase III Archives | NOAA Gulf Spill Restoration

Science.gov Websites

III Early Restoration Plan and Draft Early Restoration PEIS Executive Summary (pdf, 3.4 MB) Project Summary Table (pdf, 80 KB) Public Repositories (pdf, 113 KB) Press Release (pdf, 501 KB) Press Release

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.

Solid phase extraction of gold(III) on attapulgite modified with triocarbohydrazide prior to its determination in environmental samples by ICP-OES.

PubMed

Zhang, Li; Li, Zhenhua; Hu, Zheng; Chang, Xijun

2011-09-01

The first study on the high efficiency of triocarbohydrazide modified attapulgite as solid-phase extractant for preconcentration of trace Au(III) prior to the measurement by inductively coupled plasma optical emission spectrometry (ICP-OES) has been reported. Experimental conditions for effective adsorption of trace levels of Au(III) were optimized with respect to different experimental parameters using batch and column procedures in detail. At pH 3, Au(III) could be quantitatively adsorbed on the new sorbent, and the adsorbed Au(III) could be completely eluted from the sorbent surface by 2.0mL 1.0molL(-1) of HCl+2% CS(NH(2))(2) solution. An enrichment factor of 150 was accomplished. Moreover, common interfering ions did not interfere in both separation and determination. The maximum adsorption capacity of the sorbent for Au(III) was found to be 66.7mgg(-1). The detection limit (3σ) of this method was 0.32μgL(-1) and the relative standard deviation (RSD) was 3.3% (n=8). The method, with high selectivity, sensitivity and reproducibility, was validated using certified reference materials, and had been applied for the determination of trace Au(III) with satisfactory results. Copyright © 2011 Elsevier B.V. All rights reserved.

Chromium(iii) oxidation by biogenic manganese oxides with varying structural ripening.

PubMed

Tang, Yuanzhi; Webb, Samuel M; Estes, Emily R; Hansel, Colleen M

2014-09-20

Manganese (Mn) oxides, which are generally considered biogenic in origin within natural systems, are the only oxidants of Cr(iii) under typical environmental conditions. Yet the influence of Mn biooxide mineral structural evolution on Cr(iii) oxidation under varying geochemical conditions is unknown. In this study we examined the role of light, organic carbon, pH, and the structure of biogenic Mn oxides on Cr(iii) oxidation. Aging of Mn oxides produced by a marine bacterium within the widespread Roseobacter clade resulted in structural ripening from a colloidal hexagonal to a particulate triclinic birnessite phase. The structurally diverse Mn oxides were then reacted with aqueous Cr(iii) within artificial seawater in the presence or absence of carbon and light. Here we found that Cr(iii) oxidation capacity was highest at near neutral pH and in the combined presence of carbon and light. Mn oxide ripening from a hexagonal to a triclinic birnessite phase led to decreased Cr(iii) oxidation in the presence of carbon and light, whereas no change in reactivity was observed in the absence of carbon and/or in the dark. As only minimal Cr(iii) oxidation was observed in the absence of Mn oxides, these results strongly point to coupled Mn oxide- and photo-induced generation of organic and/or oxygen radicals involved in Cr(iii) oxidation. Based on Mn oxide concentration and structural trends, we postulate that Mn(ii) produced from the oxidation of Cr(iii) by the primary Mn oxide is recycled in the presence of organics and light conditions, (re)generating secondary hexagonal birnessite and thereby allowing for continuous oxidation of Cr(iii). In the absence of this Mn oxide regeneration, Cr(iii) induced structural ripening of the hexagonal birnessite precludes further Cr(iii) oxidation. These results highlight the complexity of reactions involved in Mn oxide mediated Cr(iii) oxidation and suggest that photochemical carbon reactions are requisite for sustained Cr(iii) oxidation and persistence of reactive Mn oxides.

Complexation Enhancement Drives Water-to-Oil Ion Transport: A Simulation Study

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

Qiao, Baofu; Ferru, Geoffroy; Ellis, Ross J.

We address the structures and energetics of ion solvation in aqueous and organic solutions to understand liquid-liquid ion transport. Atomistic molecular dynamics (MD) simulations with polarizable force field are performed to study the coordination transformations driving lanthanide (Ln(III)) and nitrate ion transport between aqueous and an alkylamide-oil solution. An enhancement of the coordination behavior in the organic phase is achieved in contrast with the aqueous solution. In particular, the coordination number of Ce3+ increases from 8.9 in the aqueous to 9.9 in the organic solutions (from 8 in the aqueous to 8.8 in the organic systems for Yb3+). Moreover, themore » local coordination environ ment changes dramatically. Potential of mean force calculations show that the Ln(III)-ligand coordination interaction strengths follow the order of Ln(III-)nitrate> Ln(III)-water>Ln(III)-DMDBTDMA. They increase 2-fold in the lipophilic environment in comparison to the aqueous phase, and we attribute this to the shedding of the outer solvation shell. Our findings highlight the importance of outer sphere interactions on the competitive solvation energetics that cause ions to migrate between immiscible phases; an essential ingredient for advancing important applications such as rare earth metal separations. Some open questions in simulating the coordination behavior of heavy metals are also addressed.« less

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

Hawkins, Cory A.; Bustillos, Christian G.; May, Iain

Conventional solvent extraction of selected f-element cations by bis(2-ethylhexyl)phosphoric acid (HDEHP) yields increased extraction from aqueous to organic solution along the series Np(V) < Cm(III) < Eu(III) < U(VI), with distribution ratios all within two orders of magnitude. However, in the presence of the water-soluble tetradentate Schiff base (N,N'-bis(5-sulfonatosalicylidene)-ethylenediamine or H 2salenSO 3), selective complexation of the two actinyl cations (Np(V) and U(VI)) resulted in an extraction order of Np(V) < U(VI) << Eu(III) < Cm(III). The extraction of neither Cm(III) or Eu(III) by HDEHP are significantly impacted by the presence of the aqueous phase Schiff base. Despite observed hydrolyticmore » decomposition of H 2salenSO 3 in aqueous solutions, the calculated high conditional stability constant (β 11 = 26) for the complex [UO 2(salenSO 3)] 2- demonstrates its capacity for aqueous hold-back of U(VI). UV-visible-NIR spectroscopy of solutions prepared with a Np(VI) stock and H 2salenSO 3 suggest that reduction of Np(VI) to Np(V) by the ligand was rapid, resulting in a pentavalent Np complex that was substantially retained in the aqueous phase. Lastly, results from 1H NMR of aqueous solutions of H 2salenSO 3 with U(VI) and La(III), Eu(III), and Lu(III) provides additional evidence that the ligand readily chelates U(VI), but has only weak interactions with trivalent lanthanide ions.« less

Immunogenicity and safety of the new reduced-dose tetanus-diphtheria vaccine in healthy Korean adolescents: A comparative active control, double-blind, randomized, multicenter phase III study.

PubMed

Han, Seung Beom; Rhim, Jung-Woo; Shin, Hye Jo; Kim, Sang Yong; Kim, Jong-Hyun; Kim, Hyun-Hee; Lee, Kyung-Yil; Kim, Hwang Min; Choi, Young Youn; Ma, Sang Hyuk; Kim, Chun Soo; Kim, Dong Ho; Ahn, Dong Ho; Kang, Jin Han

2017-04-01

A new reduced-dose tetanus-diphtheria (Td) vaccine was developed in Korea, and phase I and II clinical trials were successfully undertaken. We conducted this double-blind, randomized, multicenter phase III clinical trial to assess the immunogenicity and safety of the new Td vaccine. Healthy adolescents 11-12 years of age were enrolled and randomized to receive the new Td vaccine (study group) or a commercially available Td vaccine (control group). Blood samples were collected prior to and 4 weeks after the vaccination. Between the study and control groups, seroprotection rate, booster response, and geometric mean titer of antibodies against diphtheria and tetanus toxoids were compared after the vaccination. All solicited and unsolicited adverse events and serious adverse events during the 6-week study period were monitored. A total of 164 adolescents received vaccination, and 156 of them were evaluated to assess immunogenicity. The seroprotection rate and geometric mean titer for antibodies against diphtheria were significantly higher in the study group, whereas those against tetanus were significantly higher in the control group. However, all seroprotection rates against diphtheria and tetanus in the study and control groups were high: 100% against diphtheria and tetanus in the study group, and 98.7% against diphtheria and 100% against tetanus in the control group. No significant differences in the frequency of solicited and unsolicited adverse events were observed between the two vaccine groups. The new Td vaccine is highly immunogenic and safe, and this new Td vaccine can be effectively used for preventing diphtheria and tetanus. Copyright © 2015. Published by Elsevier B.V.

Everolimus for Previously Treated Advanced Gastric Cancer: Results of the Randomized, Double-Blind, Phase III GRANITE-1 Study

PubMed Central

Ohtsu, Atsushi; Ajani, Jaffer A.; Bai, Yu-Xian; Bang, Yung-Jue; Chung, Hyun-Cheol; Pan, Hong-Ming; Sahmoud, Tarek; Shen, Lin; Yeh, Kun-Huei; Chin, Keisho; Muro, Kei; Kim, Yeul Hong; Ferry, David; Tebbutt, Niall C.; Al-Batran, Salah-Eddin; Smith, Heind; Costantini, Chiara; Rizvi, Syed; Lebwohl, David; Van Cutsem, Eric

2013-01-01

Purpose The oral mammalian target of rapamycin inhibitor everolimus demonstrated promising efficacy in a phase II study of pretreated advanced gastric cancer. This international, double-blind, phase III study compared everolimus efficacy and safety with that of best supportive care (BSC) in previously treated advanced gastric cancer. Patients and Methods Patients with advanced gastric cancer that progressed after one or two lines of systemic chemotherapy were randomly assigned to everolimus 10 mg/d (assignment schedule: 2:1) or matching placebo, both given with BSC. Randomization was stratified by previous chemotherapy lines (one v two) and region (Asia v rest of the world [ROW]). Treatment continued until disease progression or intolerable toxicity. Primary end point was overall survival (OS). Secondary end points included progression-free survival (PFS), overall response rate, and safety. Results Six hundred fifty-six patients (median age, 62.0 years; 73.6% male) were enrolled. Median OS was 5.4 months with everolimus and 4.3 months with placebo (hazard ratio, 0.90; 95% CI, 0.75 to 1.08; P = .124). Median PFS was 1.7 months and 1.4 months in the everolimus and placebo arms, respectively (hazard ratio, 0.66; 95% CI, 0.56 to 0.78). Common grade 3/4 adverse events included anemia, decreased appetite, and fatigue. The safety profile was similar in patients enrolled in Asia versus ROW. Conclusion Compared with BSC, everolimus did not significantly improve overall survival for advanced gastric cancer that progressed after one or two lines of previous systemic chemotherapy. The safety profile observed for everolimus was consistent with that observed for everolimus in other cancers. PMID:24043745

Study protocol for the G-SPIRIT trial: a randomised, placebo-controlled, double-blinded phase III trial of granulocyte colony-stimulating factor-mediated neuroprotection for acute spinal cord injury

PubMed Central

Koda, Masao; Hanaoka, Hideki; Sato, Takatoshi; Fujii, Yasuhisa; Hanawa, Michiko; Takahashi, Sho; Furuya, Takeo; Ijima, Yasushi; Saito, Junya; Kitamura, Mitsuhiro; Ohtori, Seiji; Matsumoto, Yukei; Abe, Tetsuya; Watanabe, Kei; Hirano, Toru; Ohashi, Masayuki; Shoji, Hirokazu; Mizouchi, Tatsuki; Takahashi, Ikuko; Kawahara, Norio; Kawaguchi, Masahito; Orita, Yugo; Sasamoto, Takeshi; Yoshioka, Masahito; Fujii, Masafumi; Yonezawa, Katsutaka; Soma, Daisuke; Taneichi, Hiroshi; Takeuchi, Daisaku; Inami, Satoshi; Moridaira, Hiroshi; Ueda, Haruki; Asano, Futoshi; Shibao, Yosuke; Aita, Ikuo; Takeuchi, Yosuke; Mimura, Masaya; Shimbo, Jun; Someya, Yukio; Ikenoue, Sumio; Sameda, Hiroaki; Takase, Kan; Ikeda, Yoshikazu; Nakajima, Fumitake; Hashimoto, Mitsuhiro; Ozawa, Tomoyuki; Hasue, Fumio; Fujiyoshi, Takayuki; Kamiya, Koshiro; Watanabe, Masahiko; Katoh, Hiroyuki; Matsuyama, Yukihiro; Yamamoto, Yu; Togawa, Daisuke; Hasegawa, Tomohiko; Kobayashi, Sho; Yoshida, Go; Oe, Shin; Banno, Tomohiro; Arima, Hideyuki; Akeda, Koji; Kawamoto, Eiji; Imai, Hiroshi; Sakakibara, Toshihiko; Sudo, Akihiro; Ito, Yasuo; Kikuchi, Tsuyoshi; Osaki, Shuhei; Tanaka, Nobuhiro; Nakanishi, Kazuyoshi; Kamei, Naosuke; Kotaka, Shinji; Baba, Hideo; Okudaira, Tsuyoshi; Konishi, Hiroaki; Yamaguchi, Takayuki; Ito, Keigo; Katayama, Yoshito; Matsumoto, Taro; Matsumoto, Tomohiro; Idota, Masaru; Kanno, Haruo; Aizawa, Toshimi; Hashimoto, Ko; Eto, Toshimitsu; Sugaya, Takehiro; Matsuda, Michiharu; Fushimi, Kazunari; Nozawa, Satoshi; Iwai, Chizuo; Taguchi, Toshihiko; Kanchiku, Tsukasa; Suzuki, Hidenori; Nishida, Norihiro; Funaba, Masahiro; Yamazaki, Masashi

2018-01-01

Introduction Granulocyte colony-stimulating factor (G-CSF) is generally used for neutropaenia. Previous experimental studies revealed that G-CSF promoted neurological recovery after spinal cord injury (SCI). Next, we moved to early phase of clinical trials. In a phase I/IIa trial, no adverse events were observed. Next, we conducted a non-randomised, non-blinded, comparative trial, which suggested the efficacy of G-CSF for promoting neurological recovery. Based on those results, we are now performing a phase III trial. Methods and analysis The objective of this study is to evaluate the efficacy of G-CSF for acute SCI. The study design is a prospective, multicentre, randomised, double-blinded, placebo-controlled comparative study. The current trial includes cervical SCI (severity of American Spinal Injury Association (ASIA) Impairment Scale B/C) within 48 hours after injury. Patients are randomly assigned to G-CSF and placebo groups. The G-CSF group is administered 400 µg/m2/day×5 days of G-CSF in normal saline via intravenous infusion for 5 consecutive days. The placebo group is similarly administered a placebo. Our primary endpoint is changes in ASIA motor scores from baseline to 3 months. Each group includes 44 patients (88 total patients). Ethics and dissemination The study will be conducted according to the principles of the World Medical Association Declaration of Helsinki and in accordance with the Japanese Medical Research Involving Human Subjects Act and other guidelines, regulations and Acts. Results of the clinical study will be submitted to the head of the respective clinical study site as a report after conclusion of the clinical study by the sponsor-investigator. Even if the results are not favourable despite conducting the clinical study properly, the data will be published as a paper. Trial registration number UMIN000018752. PMID:29730616

Does Management Matter?: Using MISR to Assess the Effects of Charcoal Production and Management on Woodland Regeneration

NASA Astrophysics Data System (ADS)

Wurster, K.

2008-12-01

In much of Sub-Saharan Africa, more than 75 percent of a rapidly growing urban population depends on charcoal as their primary source of energy for cooking. The high demand for charcoal has led many to believe that charcoal harvesting catalyzes widespread deforestation. The Senegalese government and international donors have initiated projects within protected areas to combat deforestation and created land management plans to sustainably harvest charcoal. To date, the effects of forest management techniques on forest sustainability are still in question. This research uses a multiphase approach integrating satellite analysis with field surveys to assess the effect of varying forest management strategies on forest regeneration and sustainability after charcoal harvesting. Phase I involved testing the Multiangle Imaging SpectroRadiometer (MISR) satellites capability in detecting structural changes in vegetative cover caused by charcoal harvesting and production. Analysis of the MISR derived k(red) parameter showed MISR can consistently differentiate between forest cover types and successfully differentiates between sites at pre- and post-charcoal harvest stages. Phase II conducted forestry and social surveys comparing and contrasting local effects of land management, land use, and charcoal production on forest regeneration. Phase III uses the local surveys to validate and train the regional remote sensing data to assess the effectiveness of land management in promoting forest regeneration and sustainability after charcoal harvesting. Combining detailed local knowledge with the regional capabilities of MISR provide valuable insight into the factors that control woodland regeneration and sustainability. Preliminary results from phases II and III indicate that both field and remotely sensed variations in forest cover, tree regeneration, and land use change does not vary when compared against land management type. Final results will provide managers with additional information to create more effective land management strategies that can be implemented across sub- Saharan Africa, ensuring the long-term sustainability of woodland ecosystems and local livelihoods.

High-intensity interval training in patients with coronary heart disease: Prescription models and perspectives.

PubMed

Ribeiro, Paula A B; Boidin, Maxime; Juneau, Martin; Nigam, Anil; Gayda, Mathieu

2017-01-01

Recently, high-intensity interval training (HIIT) has emerged as an alternative and/or complementary exercise modality to continuous aerobic exercise training (CAET) in CHD patients. However, the literature contains descriptions of many HIIT protocols with different stage durations, nature of recovery and intensities. In this review, we discuss the most recent forms of validated HIIT protocols in patients with coronary heart disease (CHD) and how to prescribe and use them during short- and long-term (phase II and III) cardiac rehabilitation programs. We also compare the superior and/or equivalent short- and long-term effects of HIIT versus CAET on aerobic fitness, cardiovascular function, and quality of life; their efficiency, safety, and tolerance; and exercise adherence. Short interval HIIT was found beneficial for CHD patients with lower aerobic fitness and would ideally be used in initiation and improvement stages. Medium and/or long interval HIIT protocols may be beneficial for CHD patients with higher aerobic fitness, and would be ideally used in the improvement and maintenance stages because of their high physiological stimulus. Finally, we propose progressive individualized models of HIIT programs (phase II to III) for patients with CHD and how to ideally use them according to the clinical status of patients and phase of the cardiac rehabilitation program. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Levodopa Reduces the Phase lag Index of Parkinson's Disease Patients: A Magnetoencephalographic Study.

PubMed

Cao, Chunyan; Li, Dianyou; Zeng, Ke; Zhan, Shikun; Huang, Peng; Li, Xiaoli; Sun, Bomin

2018-06-01

As a method of measuring the phase difference between 2 signals, the phase lag index (PLI) of the alpha and beta bands in patients with Parkinson's disease (PD) was investigated by using magnetoencephalography (MEG). Eighteen PD patients were measured by MEG in the state of overnight withdrawal of levodopa and after levodopa treatment; meanwhile, Unified Parkinson's Disease Rating Scale (UPDRS) III scale was evaluated. Compared with healthy controls, alpha (8-13 Hz) PLI in the frontal and parietal areas elevated in PD patients, while the elevation was reversed by the levodopa treatment. The alterations of the UPDRS III total scale ( r s = 0.552, P = .013, n = 16) and the changes of akinesia scale ( r s = 0.622, P = .005, n = 16) were correlated to the change of beta (13-30 Hz) PLI in the left parietal area. The change of the UPDRS total scale was negatively correlated to duration of disease ( r s = 0.432, P = .047, n = 16). There was a negative correlation between the age of PD patients and the change of alpha PLI in the left frontal area ( r s = 0.519, P = .020, n = 16). PD patients showed a higher mu PLI in the sensorimotor area relative to the healthy controls. The improvement of motor symptoms of PD patients by levodopa was correlated to the inhibition of beta PLI in the sensorimotor area.