Case study: Use of isothiazolinone and nitro-morpholine biocides to control microbial contamination in diesel and gasoline storage and distribution systems

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

Chesneau, H.L.; Passman, F.J.; Daniels, D.

1995-05-01

Responding to feed-back from its retail outlet network, a major, vertically integrated petroleum company undertook to diagnose and remediate diesel and gasoline performance problems. Analysis of samples from tanks at refinery, distribution terminal and retail outlet sites established that uncontrolled microbial contamination was rampant throughout the distribution system. The company then developed and instituted a two-phase action plan. During Phase I, all tanks received corrective (shock) biocide treatment preceding mechanical tank cleaning and fuel polishing. An ongoing Phase II program currently includes routine sampling and analysis combined with periodic preventive biocide treatment. This paper describes the initial problem diagnosis, correctivemore » action plan and preventive program; recommending the Phase II program as a model for all companies involved with refining, distribution or retailing gasoline.« less

Esthetics evaluation

Treesearch

Victor A. Rudis; James H. Gramann; Theresa A. Herrick

1994-01-01

An analysis of summer visual attributes and an overview of ongoing scenic quality research within selected shortleaf pine-hardwood stands in the Ouachita and Ozark National forests are presented.Within-stand visual attributes were reported prior to even-aged stand-level (Phase II) treatment for twelve 40-acre stands in the north, east, and south regions and for plot-...

Search for neutrinoless double beta decay with GERDA phase II

NASA Astrophysics Data System (ADS)

Agostini, M.; Bakalyarov, A. M.; Balata, M.; Barabanov, I.; Baudis, L.; Bauer, C.; Bellotti, E.; Belogurov, S.; Bettini, A.; Bezrukov, L.; Bode, T.; Borowicz, D.; Brudanin, V.; Brugnera, R.; Caldwell, A.; Cattadori, C.; Chernogorov, A.; D'Andrea, V.; Demidova, E. V.; Di Marco, N.; Domula, A.; Doroshkevich, E.; Egorov, V.; Falkenstein, R.; Gangapshev, A.; Garfagnini, A.; Gooch, C.; Grabmayr, P.; Gurentsov, V.; Gusev, K.; Hakenmüller, J.; Hegai, A.; Heisel, M.; Hemmer, S.; Hofmann, W.; Hult, M.; Inzhechik, L. V.; Csáthy, J. Janicskó; Jochum, J.; Junker, M.; Kazalov, V.; Kihm, T.; Kirpichnikov, I. V.; Kirsch, A.; Kish, A.; Klimenko, A.; Kneißl, R.; Knies, J.; Knöpfle, K. T.; Kochetov, O.; Kornoukhov, V. N.; Kuzminov, V. V.; Laubenstein, M.; Lazzaro, A.; Lebedev, V. I.; Liao, H. Y.; Lindner, M.; Lippi, I.; Lubashevskiy, A.; Lubsandorzhiev, B.; Lutter, G.; Majorovits, B.; Maneschg, W.; Marissens, G.; Miloradovic, M.; Mingazheva, R.; Misiaszek, M.; Moseev, P.; Nemchenok, I.; Panas, K.; Pandola, L.; Pelczar, K.; Pullia, A.; Ransom, C.; Reissfelder, M.; Riboldi, S.; Rumyantseva, N.; Sada, C.; Salamida, F.; Schmitt, C.; Schneider, B.; Schönert, S.; Schreiner, J.; Schulz, O.; Schütz, A.-K.; Schwingenheuer, B.; Seitz, H.; Selivanenko, O.; Shevchik, E.; Shirchenko, M.; Simgen, H.; Smolnikov, A.; Stanco, L.; Vanhoefer, L.; Vasenko, A. A.; Veresnikova, A.; von Sturm, K.; Wagner, V.; Wegmann, A.; Wester, T.; Wiesinger, C.; Wojcik, M.; Yanovich, E.; Zhitnikov, I.; Zhukov, S. V.; Zinatulina, D.; Zuber, K.; Zuzel, G.

2017-10-01

The GERmanium Detector Array (gerda) experiment, located at the Gran Sasso underground laboratory in Italy, is one of the leading experiments for the search of 0νββ decay. In Phase II of the experiment 35.6 kg of enriched germanium detectors are operated. The application of active background rejection methods, such as a liquid argon scintillation light read-out and pulse shape discrimination of germanium detector signals, allowed to reduce the background index to the intended level of 10-3 cts/(keV.kg.yr). In the first five month of data taking 10.8 kg yr of exposure were accumulated. No signal has been found and together with data from Phase I a new limit for the neutrinoless double beta decay half-life of 76Ge of 5.3 . 1025 yr at 90% C.L. was established in June 2016. Phase II data taking is ongoing and will allow the exploration of half-lifes in the 1026 yr regime. The current status of data taking and an update on the background index are presented.

Mechanical model for filament buckling and growth by phase ordering.

PubMed

Rey, Alejandro D; Abukhdeir, Nasser M

2008-02-05

A mechanical model of open filament shape and growth driven by phase ordering is formulated. For a given phase-ordering driving force, the model output is the filament shape evolution and the filament end-point kinematics. The linearized model for the slope of the filament is the Cahn-Hilliard model of spinodal decomposition, where the buckling corresponds to concentration fluctuations. Two modes are predicted: (i) sequential growth and buckling and (ii) simultaneous buckling and growth. The relation among the maximum buckling rate, filament tension, and matrix viscosity is given. These results contribute to ongoing work in smectic A filament buckling.

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.

Increasing human dominance of tropical forests.

PubMed

Lewis, Simon L; Edwards, David P; Galbraith, David

2015-08-21

Tropical forests house over half of Earth's biodiversity and are an important influence on the climate system. These forests are experiencing escalating human influence, altering their health and the provision of important ecosystem functions and services. Impacts started with hunting and millennia-old megafaunal extinctions (phase I), continuing via low-intensity shifting cultivation (phase II), to today's global integration, dominated by intensive permanent agriculture, industrial logging, and attendant fires and fragmentation (phase III). Such ongoing pressures, together with an intensification of global environmental change, may severely degrade forests in the future (phase IV, global simplification) unless new "development without destruction" pathways are established alongside climate change-resilient landscape designs. Copyright © 2015, American Association for the Advancement of Science.

Crystal Growth of II-VI Semiconducting Alloys by Directional Solidification

NASA Technical Reports Server (NTRS)

Lehoczky, Sandor L.; Szofran, Frank R.; Su, Ching-Hua; Cobb, Sharon D.; Scripa, Rosalia A.; Sha, Yi-Gao

1999-01-01

This research study is investigating the effects of a microgravity environment during the crystal growth of selected II-VI semiconducting alloys on their compositional, metallurgical, electrical and optical properties. The on-going work includes both Bridgman-Stockbarger and solvent growth methods, as well as growth in a magnetic field. The materials investigated are II-VI, Hg(1-x)Zn(x)Te, and Hg(1-x)Zn(x)Se, where x is between 0 and 1 inclusive, with particular emphasis on x-values appropriate for infrared detection and imaging in the 5 to 30 micron wavelength region. Wide separation between the liquidus and solidus of the phase diagrams with consequent segregation during solidification and problems associated with the high volatility of one of the components (Hg), make the preparation of homogeneous, high-quality, bulk crystals of the alloys an extremely difficult nearly an impossible task in a gravitational environment. The three-fold objectives of the on-going investigation are as follows: (1) To determine the relative contributions of gravitationally-driven fluid flows to the compositional redistribution observed during the unidirectional crystal growth of selected semiconducting solid solution alloys having large separation between the liquidus and solidus of the constitutional phase diagram; (2) To ascertain the potential role of irregular fluid flows and hydrostatic pressure effects in generation of extended crystal defects and second-phase inclusions in the crystals; and, (3) To obtain a limited amount of "high quality" materials needed for bulk crystal property characterizations and for the fabrication of various device structures needed to establish ultimate material performance limits. The flight portion of the study was to be accomplished by performing growth experiments using the Crystal Growth Furnace (CGF) manifested to fly on various Spacelab missions.

The GERDA experiment: results and perspectives

NASA Astrophysics Data System (ADS)

Macolino, Carla; Gerda Collaboration

2014-11-01

The Germanium Detector Array, GERDA, at Laboratori Nazionali del Gran Sasso (Italy), is designed to search for Majorana neutrinos via neutrinoless double beta (0νββ) decay of 76Ge. GERDA completed the Phase I in 2013, after an exposure of 21.6 kg·yr and with a background of about 0.01 cts/(keVkgyr): no signal was found and a limit on the half-life of T0ν1/2 > 2.1 · 1025 yr (90% C.L.) was established. The previous claim of 0νββ observation for 76Ge is strongly disfavoured in a model independent way. The commission for GERDA Phase II is currently ongoing and about 20 kg of additional enriched Ge diodes will be deployed. Pulse- shape analysis, together with the liquid argon instrumentation will allow to reach a background level one order of magnitude lower than in Phase I. In this paper the measurement of the half-life of 0νββ decay from GERDA Phase I and the expected sensitivity for Phase II are discussed.

Muon Physics at Run-I and its upgrade plan

NASA Astrophysics Data System (ADS)

Benekos, Nektarios Chr.

2015-05-01

The Large Hadron Collider (LHC) and its multi-purpose Detector, ATLAS, has been operated successfully at record centre-of-mass energies of 7 and TeV. After this successful LHC Run-1, plans are actively advancing for a series of upgrades, culminating roughly 10 years from now in the high luminosity LHC (HL-LHC) project, delivering of order five times the LHC nominal instantaneous luminosity along with luminosity leveling. The final goal is to extend the data set from about few hundred fb-1 expected for LHC running to 3000 fb-1 by around 2030. To cope with the corresponding rate increase, the ATLAS detector needs to be upgraded. The upgrade will proceed in two steps: Phase I in the LHC shutdown 2018/19 and Phase II in 2023-25. The largest of the ATLAS Phase-1 upgrades concerns the replacement of the first muon station of the highrapidity region, the so called New Small Wheel. This configuration copes with the highest rates expected in Phase II and considerably enhances the performance of the forward muon system by adding triggering functionality to the first muon station. Prospects for the ongoing and future data taking are presented. This article presents the main muon physics results from LHC Run-1 based on a total luminosity of 30 fb^-1. Prospects for the ongoing and future data taking are also presented. We will conclude with an update of the status of the project and the steps towards a complete operational system, ready to be installed in ATLAS in 2018/19.

Phase II study of docetaxel in combination with epirubicin and protracted venous infusion 5-fluorouracil (ETF) in patients with recurrent or metastatic breast cancer. A Yorkshire breast cancer research group study.

PubMed

Humphreys, A C; Dent, J; Rodwell, S; Crawford, S M; Joffe, J K; Bradley, C; Dodwell, D; Perren, T J

2004-06-01

This study was originally designed as a phase I/II study, with a dose escalation of docetaxel in combination with epirubicin 50 mg m(-2) and 5-fluorouracil (5-FU) 200 mg m(-2) day(-1). However, as dose escalation was not possible, the study is reported as a phase II study of the combination to assess response and toxicity. A total of 51 patients with locally advanced or metastatic breast cancer were treated on this phase II study, with doses of docetaxel 50 mg m(-2), epirubicin 50 mg m(-2) and infusional 5-FU 200 mg m(-2) day(-1) for 21 days. The main toxicity of this combination was neutropenia with 89% of patients having grade 3 and 4 neutropenia, and 39% of patients experiencing febrile neutropenia. Nonhaematological toxicity was mild. The overall response rate in the assessable patients was 64%, with median progression-free survival of 38 weeks, and median survival of 70 weeks. The ETF regimen was found to be toxic, and it was not possible to escalate the dose of docetaxel above the first dose level. This regimen has therefore not been taken any further, but as a development of this a new study is ongoing, combining 3-weekly epirubicin, weekly docetaxel and capecitabine, days 1-14.

Pre-cue Fronto-Occipital Alpha Phase and Distributed Cortical Oscillations Predict Failures of Cognitive Control

PubMed Central

Hamm, Jordan P.; Dyckman, Kara A.; McDowell, Jennifer E.; Clementz, Brett A.

2012-01-01

Cognitive control is required for correct performance on antisaccade tasks, including the ability to inhibit an externally driven ocular motor repsonse (a saccade to a peripheral stimulus) in favor of an internally driven ocular motor goal (a saccade directed away from a peripheral stimulus). Healthy humans occasionally produce errors during antisaccade tasks, but the mechanisms associated with such failures of cognitive control are uncertain. Most research on cognitive control failures focuses on post-stimulus processing, although a growing body of literature highlights a role of intrinsic brain activity in perceptual and cognitive performance. The current investigation used dense array electroencephalography and distributed source analyses to examine brain oscillations across a wide frequency bandwidth in the period prior to antisaccade cue onset. Results highlight four important aspects of ongoing and preparatory brain activations that differentiate error from correct antisaccade trials: (i) ongoing oscillatory beta (20–30Hz) power in anterior cingulate prior to trial initiation (lower for error trials), (ii) instantaneous phase of ongoing alpha-theta (7Hz) in frontal and occipital cortices immediately before trial initiation (opposite between trial types), (iii) gamma power (35–60Hz) in posterior parietal cortex 100 ms prior to cue onset (greater for error trials), and (iv) phase locking of alpha (5–12Hz) in parietal and occipital cortices immediately prior to cue onset (lower for error trials). These findings extend recently reported effects of pre-trial alpha phase on perception to cognitive control processes, and help identify the cortical generators of such phase effects. PMID:22593071

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

PubMed

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

2011-04-01

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

Invasive Cortical Stimulation to Promote Recovery of Function After Stroke

PubMed Central

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

2011-01-01

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

Modular C3 Interface Analysis (Flexible Intraconnect). Volume 1, Part 1

DTIC Science & Technology

1980-04-01

was prepared in parallel with a separate Flexible^ Intraconnect design definition study conducted by Hughes Aircraft Company under F19628-77-O-0261...reported herein consists of Task I, Task II, and Task III of Phase I of an on-going study being conducted by the Air Force to develop a Flexible...Intraconnect for tactical C^ tivity. equipment connec- As evidenced by the quantity of analyses performed and docu- mented during the period of this study

Hydration of copper(II): new insights from density functional theory and the COSMO solvation model.

PubMed

Bryantsev, Vyacheslav S; Diallo, Mamadou S; van Duin, Adri C T; Goddard, William A

2008-09-25

The hydrated structure of the Cu(II) ion has been a subject of ongoing debate in the literature. In this article, we use density functional theory (B3LYP) and the COSMO continuum solvent model to characterize the structure and stability of [Cu(H2O)n](2+) clusters as a function of coordination number (4, 5, and 6) and cluster size (n = 4-18). We find that the most thermodynamically favored Cu(II) complexes in the gas phase have a very open four-coordinate structure. They are formed from a stable square-planar [Cu(H2O)8](2+) core stabilized by an unpaired electron in the Cu(II) ion d(x(2)-y(2)) orbital. This is consistent with cluster geometries suggested by recent mass-spectrometric experiments. In the aqueous phase, we find that the more compact five-coordinate square-pyramidal geometry is more stable than either the four-coordinate or six-coordinate clusters in agreement with recent combined EXAFS and XANES studies of aqueous solutions of Cu(II). However, a small energetic difference (approximately 1.4 kcal/mol) between the five- and six-coordinate models with two full hydration shells around the metal ion suggests that both forms may coexist in solution.

Early investigational tubulin inhibitors as novel cancer therapeutics.

PubMed

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

2016-08-01

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

Evaluating the role of phase I expansion cohorts in oncologic drug development.

PubMed

Norris, Robin E; Behtaj, Mohadese; Fu, Pingfu; Dowlati, Afshin

2017-02-01

Importance Use of expansion cohorts (EC) in phase I trials is increasing. However, the utility of phase I EC in aiding drug development is unclear. We sought to determine factors associated with the inclusion of EC in phase I studies and the impact of EC on subsequent clinical development. Methods We performed a systematic review of all phase I trials published in the Journal of Clinical Oncology between June 2004 and May 2014. Presence of an EC, number of participants, funding source, class of agent, tumor type, and maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D) were identified. Subsequent conduct of phase II studies and FDA approval of the study agent was also assessed. Results We identified 252 phase I studies. An EC was included in 105 studies. Average accrual on EC studies was 47 compared to 31 in studies without EC (p < 0.0001). There was no impact of time on the inclusion of EC. Only 4 % of phase I studies with an EC provided sample size justification. Source of funding had the only significant association with inclusion of EC. Addition of a phase I EC did not impact the phase I MTD/RP2D, subsequent phase II trial, or FDA approval. Conclusion The importance of including an EC in phase I trials is subject to ongoing debate. Our results demonstrated little benefit to including EC in phase I studies. These findings support that innovative design strategies are needed to optimize the utility of EC in phase I studies.

An observational study of the hand hygiene initiative: a comparison of preintervention and postintervention outcomes

PubMed Central

Mukerji, Amit; Narciso, Janet; Moore, Christine; McGeer, Allison; Kelly, Edmond; Shah, Vibhuti

2013-01-01

Objectives To evaluate the impact of implementing a simple, user-friendly eLearning module on hand hygiene (HH) compliance and infection rates. Design Preintervention and postintervention observational study. Participants All neonates admitted to the neonatal intensive care unit (NICU) over the study period were eligible for participation and were included in the analyses. A total of 3422 patients were admitted over a 36-month span (July 2009 to June 2012). Interventions In the preintervention and postintervention periods (phases I and II), all healthcare providers were trained on HH practices using an eLearning module. The principles of the ‘4 moments of HH’ and definition of ‘baby space’ were incorporated using interactive tools. The intervention then extended into a long-term sustainability programme (phase III), including the requirement of an annual recertification of the module and introduction of posters and screensavers throughout the NICU. Primary and secondary outcome measures The primary outcome was HH compliance rates among healthcare providers in the three phases. The secondary outcome was healthcare-associated infection rates in the NICU. Results HH compliance rates declined initially in phase II then improved in phase III with the addition of a long-term sustainability programme (76%, 67% and 76% in phases I, II and III, respectively (p<0.01). Infection rates showed an opposing, but concomitant trend in the overall population as well as in infants <1500 g and were 4%, 6% and 4% (p=0.02), and 11%, 21% and 16% (p<0.01), respectively, during the three phases. Conclusions Interventions to improve HH compliance are challenging to implement and sustain with the need for ongoing reinforcement and education. PMID:23793705

Deep Bore Storage of Nuclear Waste Using MMW (Millimeter Wave) Technology, STTR Fast Track Project, Phase I Final Report-Revised

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

Oglesby, Kenneth D.; Woskov, Paul; Einstein, Herbert

This report covers the technical work in Phase I of this DOE-Nuclear Program STTR Fast Track project. All key tasks were successfully performed, new tasks were added to utilize DOD-AFRL’s 95 GigaHertz (GHz) gyrotron in Phase II, while other lesser tasks were left for Phase II efforts or were requested to be made optional. This research adds to our understanding of using MMW power to melt and vaporize rocks and steel/ metals and laid plans for future testing in Phase II. This work built upon a prior DOE project DE-EE0005504 that developed the basic waveguide setup, process and instruments. Inmore » this project we were investigating the use of MMW to form rock melt and steel plugs in deep wells to further isolate highly radioactive nuclear waste in ultra-deep basement rocks for long term storage. This technology also has potential for deep well drilling for nuclear storage, geothermal and oil and gas industries. It also has the potential for simultaneously sealing and securing the wellbore with a thick rock melt liner as the wellbore is drilled. This allows for higher levels of safety and protection of the environment during deep drilling operations. The larger purpose of this project was to find answers to key questions in progressing MMW technology for these applications. Phase I of this project continued bench testing using the MIT 10 kilo-Watt (kW), 28 GHz frequency laboratory gyrotron, literature searches, planning and design of equipment for Phase II efforts. Furnace melting and rock testing (Tasks 4 and 5) were deferred to Phase II due to lack of concurrent availability of the furnace and personnel at MIT. That delay and lower temperature furnace (limited to 1650oC) caused rethinking of Task 4 to utilize coordinated rock selection with the DOD testing in Phase II. The high pressure and high power window design work (moved to Phase I Task 3 from Phase II Task 20) and Additive materials and methods (Tasks 7 & 8) performed in Phase I may become patentable and thus little detail can be provided in this public report. A version of that new high pressure, high MMW power window may be built for possible Phase II testing at the DOD site. Most significantly, additional tasks were added for planning the use of the Department of Defense, Air Force Research Laboratory’s (DOD-AFRL’s) System 0 gyrotron in Phase II. Specifically added and accomplished were multiple discussions on DOD and DOE-MIT-Impact goals, timing between ongoing DOD testing, outlining the required equipment and instruments for rock testing, and terms for an agreement. That addition required a visit to Kirtland AFB in Albuquerque, New Mexico to talk to key DOD-AFRL personnel and management. A DOD-Impact-MIT charter (i.e., contract) is now being circulated for signatures. Also added task to Phase I, MIT designed the critical path reflected power isolator screen for Phase II testing. To ensure compatibility, that design was computer simulated for the expected heat load distribution and the resulting temperature increase. Advancing the MMW testing up to the optimum 95 GHz and 100kW (5X higher) power levels was stated in the original proposal to be a key required development step for this technology to achieve prototype drilling, lining, and rock melting/ vaporization for creating sealing plugs.« less

Ongoing developments in RSV prophylaxis: a clinician's analysis.

PubMed

Rezaee, Fariba; Linfield, Debra T; Harford, Terri J; Piedimonte, Giovanni

2017-06-01

Respiratory syncytial virus (RSV) is the most common respiratory pathogen in infants and young children worldwide. Lower respiratory tract infection due to RSV is one of the most common causes of hospitalization for infants, especially those born premature or with chronic lung or heart disease. Furthermore, RSV infection is an important cause of morbidity in adults, particularly in the elderly and immunocompromised individuals. The acute phase of this infection is often followed by episodes of wheezing that recur for months or years and usually lead to a physician diagnosis of asthma. RSV was discovered more than 50 years ago, and despite extensive research to identify pharmacological therapies, the most effective management of this infection remains supportive care. The trial of a formalin-inactivated RSV vaccine in the 1960s resulted in priming the severe illness upon natural infection. Currently, Palivizumab is the only available option for RSV prophylaxis, and because of restricted clinical benefits and high costs, it has been limited to a group of high-risk infants. There are several ongoing trials in preclinical, Phase-I, Phase-II, or Phase-III clinical stages for RSV vaccine development based on various strategies. Here we review the existing available prophylactic options, the current stages of RSV vaccine clinical trials, different strategies, and major hurdles in the development of an effective RSV vaccine. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

Minimally invasive surgery for intracerebral haemorrhage.

PubMed

Barnes, Benjamin; Hanley, Daniel F; Carhuapoma, Juan R

2014-04-01

Spontaneous intracerebral haemorrhage (ICH) imposes a significant health and economic burden on society. Despite this, ICH remains the only stroke subtype without a definitive treatment. Without a clearly identified and effective treatment for spontaneous ICH, clinical practice varies greatly from aggressive surgery to supportive care alone. This review will discuss the current modalities of treatments for ICH including preliminary experience and investigative efforts to advance the care of these patients. Open surgery (craniotomy), prothrombotic agents and other therapeutic interventions have failed to significantly improve the outcome of these stroke victims. Recently, the Surgical Trial in Intracerebral Haemorrhage (STICH) II assessed the surgical management of patients with superficial intraparenchymal haematomas with negative results. MISTIE II and other trials of minimally invasive surgery (MIS) have shown promise for improving patient outcomes and a phase III trial started in late 2013. ICH lacks a definitive primary treatment as well as a therapy targeting surrounding perihematomal oedema and associated secondary damage. An ongoing phase III trial using MIS techniques shows promise for providing treatment for these patients.

Towards a unified understanding of event-related changes in the EEG: the firefly model of synchronization through cross-frequency phase modulation.

PubMed

Burgess, Adrian P

2012-01-01

Although event-related potentials (ERPs) are widely used to study sensory, perceptual and cognitive processes, it remains unknown whether they are phase-locked signals superimposed upon the ongoing electroencephalogram (EEG) or result from phase-alignment of the EEG. Previous attempts to discriminate between these hypotheses have been unsuccessful but here a new test is presented based on the prediction that ERPs generated by phase-alignment will be associated with event-related changes in frequency whereas evoked-ERPs will not. Using empirical mode decomposition (EMD), which allows measurement of narrow-band changes in the EEG without predefining frequency bands, evidence was found for transient frequency slowing in recognition memory ERPs but not in simulated data derived from the evoked model. Furthermore, the timing of phase-alignment was frequency dependent with the earliest alignment occurring at high frequencies. Based on these findings, the Firefly model was developed, which proposes that both evoked and induced power changes derive from frequency-dependent phase-alignment of the ongoing EEG. Simulated data derived from the Firefly model provided a close match with empirical data and the model was able to account for i) the shape and timing of ERPs at different scalp sites, ii) the event-related desynchronization in alpha and synchronization in theta, and iii) changes in the power density spectrum from the pre-stimulus baseline to the post-stimulus period. The Firefly Model, therefore, provides not only a unifying account of event-related changes in the EEG but also a possible mechanism for cross-frequency information processing.

Towards a Unified Understanding of Event-Related Changes in the EEG: The Firefly Model of Synchronization through Cross-Frequency Phase Modulation

PubMed Central

Burgess, Adrian P.

2012-01-01

Although event-related potentials (ERPs) are widely used to study sensory, perceptual and cognitive processes, it remains unknown whether they are phase-locked signals superimposed upon the ongoing electroencephalogram (EEG) or result from phase-alignment of the EEG. Previous attempts to discriminate between these hypotheses have been unsuccessful but here a new test is presented based on the prediction that ERPs generated by phase-alignment will be associated with event-related changes in frequency whereas evoked-ERPs will not. Using empirical mode decomposition (EMD), which allows measurement of narrow-band changes in the EEG without predefining frequency bands, evidence was found for transient frequency slowing in recognition memory ERPs but not in simulated data derived from the evoked model. Furthermore, the timing of phase-alignment was frequency dependent with the earliest alignment occurring at high frequencies. Based on these findings, the Firefly model was developed, which proposes that both evoked and induced power changes derive from frequency-dependent phase-alignment of the ongoing EEG. Simulated data derived from the Firefly model provided a close match with empirical data and the model was able to account for i) the shape and timing of ERPs at different scalp sites, ii) the event-related desynchronization in alpha and synchronization in theta, and iii) changes in the power density spectrum from the pre-stimulus baseline to the post-stimulus period. The Firefly Model, therefore, provides not only a unifying account of event-related changes in the EEG but also a possible mechanism for cross-frequency information processing. PMID:23049827

Long-acting rilpivirine for HIV prevention.

PubMed

Jackson, Akil; McGowan, Ian

2015-07-01

Long-acting injectable antiretroviral (ARV) formulations are being developed for the treatment and prevention of HIV infection. The purpose of this review is to summarize recent preclinical and clinical data on TMC278 (rilpivirine), a nonnucleoside reverse transcriptase inhibitor (NNRTI), that is being developed for both a treatment and prevention indication. Long-acting rilpivirine has demonstrated efficacy in preventing HIV acquisition in a humanized mouse model and has been found to be well tolerated and acceptable in several Phase I clinical trials. Pharmacokinetic data from Phase I studies suggest that 1200 mg of long-acting rilpivirine administered every 8 weeks would be associated with plasma and tissue levels of rilpivirine anticipated to be necessary for preventing HIV infection. This regimen is being evaluated in the HPTN-076 Phase II expanded safety study that will enroll women in South Africa, Zimbabwe, and the USA. The HPTN-076 study requires a 4-week run in with oral rilpivirine (25 mg capsules) before receiving 1200 mg of rilpivirine. It is not yet certain whether oral dosing will remain a prerequisite in future trials or post licensure. Long-acting rilpivirine shows promise as a candidate agent for HIV prevention. Preclinical efficacy has been demonstrated in a murine model. Phase I studies have shown good safety and efficacy, but breakthrough infection and resistance have been documented with lower doses of long-acting rilpivirine. Phase II development for a prevention indication is ongoing.

A randomized double-blinded controlled trial of hCG as luteal phase support in natural cycle frozen embryo transfer.

PubMed

Lee, Vivian Chi Yan; Li, Raymond Hang Wun; Yeung, William Shu Biu; Pak Chung, H O; Ng, Ernest Hung Yu

2017-05-01

Does the use of hCG as luteal phase support in natural cycle frozen embryo transfer (FET) increase the ongoing pregnancy rate? The use of hCG in natural cycle FET did not improve the ongoing pregnancy rate. The use of luteal phase support in stimulated cycles has been associated with higher live-birth rates and the results are similar when using hCG or progesterone. This is a randomized double-blinded controlled trial of 450 women recruited between August 2013 and October 2015. Women with regular cycles undergoing natural cycle FET were recruited. Serial serum hormonal concentrations were used to time natural ovulation and at least Day 2 cleavage embryos were replaced. Patients were randomized into either: (i) the treatment group, receiving 1500 IU hCG on the day of FET and 6 days after FET, or (ii) the control group, receiving normal saline on these 2 days. The ongoing pregnancy rate [60/225 (26.7%) in the treatment group vs 70/225 (31.3%) in the control group, odds ratio 1.242 (95% CI 0.825-1.869)], implantation rate and miscarriage rate were comparable between the two groups. In the treatment group, there were significantly more cycles with top quality embryos transferred and a significantly higher serum oestradiol level, but a comparable serum progesterone level, 6 days after FET. However, no significant differences were observed in serum oestradiol and progesterone levels 6 days after FET between the pregnant and non-pregnant women. In the multivariate logistic regression, the number of embryos transferred was the only significant factor predictive of the ongoing pregnancy rate after natural cycle FET. This study only included FET with cleavage stage embryos and only hCG, not vaginal progesterone, was used as luteal phase support. The findings in this study do not support the use of hCG for luteal phase support in natural cycle FET. No external funding was used and there were no competing interests. clinicaltrial.gov identifier: NCT01931384. 23/8/2013. 30/8/2013. © The Author 2017. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com

Review of ongoing clinical trials in non-small-cell lung cancer: a status report for 2012 from the ClinicalTrials.gov Web site.

PubMed

Subramanian, Janakiraman; Regenbogen, Thomas; Nagaraj, Gayathri; Lane, Alex; Devarakonda, Siddhartha; Zhou, Gongfu; Govindan, Ramaswamy

2013-07-01

Clinical research in non-small-cell lung cancer (NSCLC) is a rapidly evolving field. In an effort to identify the current trends in lung cancer clinical research, we reviewed ongoing clinical trials in NSCLC listed in the ClinicalTrials.gov registry in 2012, and we also compared this data to a similar survey conducted by us in 2009. The Web site's advanced search function was used to search for the term "non-small cell lung cancer." The search was further refined by using the following options from the search page drop-down menu, "open studies" and "interventional." Studies with non-NSCLC tumor histologies and pediatric studies were excluded. Of the 477 trials included in the analysis, 105 (22.0%) were phase I, 223 phase II (46.8%), and 63 phase III trials (13.2%). When compared with data from 2009, university-sponsored trials decreased in number (45.4%-34.2%; p < 0.001) whereas industry-sponsored trials remained almost the same. There was a significant increase in trials conducted exclusively outside of the United States (35.9%-48.8%; p = 0.001). The number of studies with locations in China (61, 12.8%) was second only to that in the United States (244, 51.2%). Studies reporting biomarker analysis increased significantly from 37.5% to 49.1% in 2012 (p < 0.001). Biomarker-based patient selection also increased significantly from 7.9% to 25.8% (p < 0.001). Targeted therapies were evaluated in 70.6% of phase I/II and II trials, and the most common class of targeted agent studied was epidermal growth factor receptor tyrosine kinase inhibitors (38.0%). Prespecified accrual times were observed to increase when compared with data reported in 2009, especially among industry-sponsored studies. Our survey identified major changes in lung cancer clinical research since 2009. Almost half of all studies registered at the ClinicalTrials.gov Web site are being conducted outside the United States, and several novel molecularly targeted agents are being evaluated in the treatment of patients with NSCLC. More importantly, we identified a threefold increase in the number of studies that perform biomarker testing to determine patient selection over the last 3 years.

Thrombopoietic agents.

PubMed

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

2010-01-01

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

The development and refinement of models of less established and more established high school environmental service-learning programs in Florida

NASA Astrophysics Data System (ADS)

Malikova, Yuliya

2005-07-01

Environmental Service-Learning (Env. S-L) appears to show great promise and practitioners tout its benefits, although there have been fewer than ten studies in this emerging area of environmental education. The overall study purpose was to describe the nature, status, and effects of Grade 9--16 Env. S-L programs in Florida, and develop descriptive models of those programs. The purpose of Phase I was to describe these programs and associated partnerships. Based on Phase I results, the purpose of Phase II was to develop, compare, and refine models for less and more established high school programs. This study involved: (1) defining the population of Florida 9--16 Env. S-L programs (Phase I); (2) developing and administering program surveys (Phase I, quantitative); (3) analyzing Phase I survey data and identifications of options for Phase II (Intermediate stage); (4) designing and implementing methodology for further data collection (Phase II, qualitative); (5) refining and finalizing program models (Phase II, descriptive); and (6) summarizing program data, changes, and comparisons. This study revealed that Env. S-L has been practiced in a variety of ways at the high school and college levels in Florida. There, the number of high school programs, and participating teachers and students has been growing. Among others, major program features include block scheduling, indirect S-L activities, external funding sources, and formal and ongoing community partnerships. Findings based on self-reported program assessment results indicate that S-L has had positive effects on students across Furco's S-L outcome domains (i.e., academic achievement/success, school participation/behavior, carrier development, personal development, interpersonal development, ethical/moral development, and development of civic responsibility). Differences existed between less established and more established Env. S-L programs. Less established programs had relatively few participating teachers, courses, projects, community partners, and service sites. Most S-L activities were offered as electives. Lead teachers used reflection to integrate academic learning with service experience to a moderate extent. More established programs had a larger number of participating teachers, courses, projects, community partners, partner representatives, and service sites. Students were consistently engaged in multiple forms of reflection. These teachers also practiced S-L before their exposure to the wider field of S-L.

Photonic Network R&D Activities in Japan-Current Activities and Future Perspectives

NASA Astrophysics Data System (ADS)

Kitayama, Ken-Ichi; Miki, Tetsuya; Morioka, Toshio; Tsushima, Hideaki; Koga, Masafumi; Mori, Kazuyuki; Araki, Soichiro; Sato, Ken-Ichi; Onaka, Hiroshi; Namiki, Shu; Aoyama, Tomonori

2005-10-01

R&D activities on photonic networks in Japan are presented. First, milestones in current ongoing R&D programs supported by Japanese government agencies are introduced, including long-distance and wavelength division multiplexing (WDM) fiber transmission, wavelength routing, optical burst switching (OBS), and control-plane technology for IP backbone networks. Their goal was set to evolve a legacy telecommunications network to IP-over-WDM networks by introducing technologies for WDM and wavelength routing. We then discuss the perspectives of so-called PHASE II R&D programs for photonic networks over the next 5 years until 2010, by focusing on the report that has been recently issued by the Photonic Internet Forum (PIF), a consortium that has major carriers, telecom vendors, and Japanese academics as members. The PHASE II R&D programs should serve to establish a photonic platform to provide abundant bandwidth on demand, at any time on a real-time basis, through the customer's initiative to promote bandwidth-rich applications, such as grid computing, real-time digital-cinema streaming, medical and educational applications, and network storage in e-commerce.

Photonic network R and D activities in Japan

NASA Astrophysics Data System (ADS)

Kitayama, Ken-ichi; Miki, Tetsuya; Morioka, Toshio; Tsushima, Hideaki; Koga, Masafumi; Mori, Kazuyuki; Araki, Soichiro; Sato, Ken-ichi; Onaka, Hiroshi; Namiki, Shu; Aovama, Tomonori

2005-11-01

R and D activities on photonic networks in Japan are presented. First, milestones in current, ongoing R and D programs supported by Japanese government agencies are introduced, including long-distance and WDM fiber transmission, wavelength routing, optical burst switching, and control plane technology for IP backbone networks. Their goal was set to evolve a legacy telecommunications network to IP over WDM networks by introducing technologies for WDM and wavelength routing. We then discuss the perspectives of so-called PHASE II R and D programs for photonic networks over the next five years until 2010, by focusing on the report which has been recently issued by the Photonic Internet Forum (PIF), a consortium that has major carriers, telecom vendors, and Japanese academics as members. The PHASE II R and D programs should serve to establish a photonic platform to provide abundant bandwidth on demand, at any time on a real-time basis through the customer's initiative, to promote bandwidth-rich applications, such as grid computing, real-time digital-cinema streaming, medical and educational applications, and network storage in e-commerce.

PROSTVAC® targeted immunotherapy candidate for prostate cancer.

PubMed

Shore, Neal D

2014-01-01

Targeted immunotherapies represent a valid strategy for the treatment of metastatic castrate-resistant prostate cancer. A randomized, double-blind, Phase II clinical trial of PROSTVAC® demonstrated a statistically significant improvement in overall survival and a large, global, Phase III trial with overall survival as the primary end point is ongoing. PROSTVAC immunotherapy contains the transgenes for prostate-specific antigen and three costimulatory molecules (designated TRICOM). Research suggests that PROSTVAC not only targets prostate-specific antigen, but also other tumor antigens via antigen cascade. PROSTVAC is well tolerated and has been safely combined with other cancer therapies, including hormonal therapy, radiotherapy, another immunotherapy and chemotherapy. Even greater benefits of PROSTVAC may be recognized in earlier-stage disease and low-disease burden settings where immunotherapy can trigger a long-lasting immune response.

Architectural Design for European SST System

NASA Astrophysics Data System (ADS)

Utzmann, Jens; Wagner, Axel; Blanchet, Guillaume; Assemat, Francois; Vial, Sophie; Dehecq, Bernard; Fernandez Sanchez, Jaime; Garcia Espinosa, Jose Ramon; Agueda Mate, Alberto; Bartsch, Guido; Schildknecht, Thomas; Lindman, Niklas; Fletcher, Emmet; Martin, Luis; Moulin, Serge

2013-08-01

The paper presents the results of a detailed design, evaluation and trade-off of a potential European Space Surveillance and Tracking (SST) system architecture. The results have been produced in study phase 1 of the on-going "CO-II SSA Architectural Design" project performed by the Astrium consortium as part of ESA's Space Situational Awareness Programme and are the baseline for further detailing and consolidation in study phase 2. The sensor network is comprised of both ground- and space-based assets and aims at being fully compliant with the ESA SST System Requirements. The proposed ground sensors include a surveillance radar, an optical surveillance system and a tracking network (radar and optical). A space-based telescope system provides significant performance and robustness for the surveillance and tracking of beyond-LEO target objects.

Superconductivity in ThPd2Ge2

NASA Astrophysics Data System (ADS)

Domieracki, Krzysztof; Wiśniewski, Piotr; Wochowski, Konrad; Romanova, Tetiana; Hackemer, Alicja; Gorzelniak, Roman; Pikul, Adam; Kaczorowski, Dariusz

2018-05-01

Our on-going search for unconventional superconductors among the ThTE2Ge2 phases (TE is a d-electron transition metal) revealed that ThPd2Ge2, which crystallizes with a body-centered tetragonal ThCr2Si2-type structure, exhibits superconductivity at low temperatures. In this paper, we report on the electrical transport and thermodynamic properties of a polycrystalline sample of this new superconductor, extended down to 50 mK. The experimental data indicates weakly-coupled type-II superconductivity with Tc = 0.63(2) K and μ0Hc2(0) = 32(2) mT.

Necitumumab, a fully human IgG1 mAb directed against the EGFR for the potential treatment of cancer.

PubMed

Dienstmann, Rodrigo; Tabernero, Josep

2010-12-01

Necitumumab (IMC-11F8), under development by ImClone Systems in collaboration with Bristol-Myers Squibb, is a fully human IgG1 mAb targeting the epidermal growth factor receptor (EGFR), for the potential intravenous treatment of cancer, in particular NSCLC. In vitro studies demonstrate that necitumumab inhibits downstream targets in the EGFR pathway (eg, MAPK), which are important for cellular proliferation, differentiation, invasion and metastasis. Furthermore, because necitumumab is an IgG1 construct, it has the potential to induce antibody-dependent cell-mediated cytotoxicity against tumor cells. Preclinical studies indicated that the antitumor activity of necitumumab is either comparable with or superior to that of ImClone's chimeric anti-EGFR mAb cetuximab. In a phase I clinical trial in patients with advanced solid malignancies, necitumumab displayed nonlinear pharmacokinetic behavior. The toxicity profile of necitumumab is acceptable, with skin toxicity being the most frequently reported adverse event in the phase I and II clinical trials conducted to date. Preliminary data from a phase II clinical trial of necitumumab in combination with chemotherapy for the first-line treatment of advanced colon cancer are promising. Success in the ongoing phase III clinical trials in patients with advanced NSCLC would lead to necitumumab becoming a valuable addition to future therapeutic strategies in oncology.

INDEPENDENT REVIEW OF THE X-701B GROUNDWATER REMEDY, PORTSMOUTH, OHIO: TECHNICAL EVALUATION AND RECOMMENDATIONS

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

Looney, B.; Eddy-Dilek, C.; Costanza, J.

2008-12-15

The Department of Energy Portsmouth Paducah Project Office requested assistance from Department of Energy Office of Environmental Management (EM-22) to provide independent technical experts to evaluate past and ongoing remedial activities at the Portsmouth facility that were completed to address TCE contamination associated with the X-701B groundwater plume and to make recommendations for future efforts. The Independent Technical Review team was provided with a detailed and specific charter. The charter requested that the technical team first review the past and current activities completed for the X-701B groundwater remedy for trichloroethene (TCE) in accordance with a Decision Document that was issuedmore » by Ohio EPA on December 8, 2003 and a Work Plan that was approved by Ohio EPA on September 22, 2006. The remedy for X-701B divides the activities into four phases: Phase I - Initial Source Area Treatment, Phase II - Expanded Source Area Treatment, Phase III - Evaluation and Reporting, and Phase IV - Downgradient Remediation and Confirmation of Source Area Treatment. Phase I of the remedy was completed during FY2006, and DOE has now completed six oxidant injection events within Phase II. The Independent Technical Review team was asked to evaluate Phase II activities, including soil and groundwater results, and to determine whether or not the criteria that were defined in the Work Plan for the Phase II end point had been met. The following criteria are defined in the Work Plan as an acceptable Phase II end point: (1) Groundwater samples from the identified source area monitoring wells have concentrations below the Preliminary Remediation Goal (PRG) for TCE in groundwater, or (2) The remedy is no longer effective in removing TCE mass from the source area. In addition, the charter specifies that if the Review Team determines that the Phase II endpoint has not been reached, then the team should address the following issues: (1) If additional injection events are recommended, the team should identify the type of injection and target soil horizon for these injections; (2) Consider the feasibility of declaring Technical Impracticability and proceeding with the RCRA Cap for the X-701B; and (3) Provide a summary of other cost-effective technologies that could be implemented (especially for the lower Gallia). The Independent Technical Review team focused its evaluation solely on the X-701B source zone and contaminant plume. It did not review current or planned remedial activities at other plumes, waste areas, or landfills at the Portsmouth site, nor did it attempt to integrate such activities into its recommendations for X-701B. However, the ultimate selection of a remedy for X-701B by site personnel and regulators should take into account potentially synergistic efforts at other waste areas. Assessment of remedial alternatives in the context of site-wide management practices may reveal opportunities for leveraging and savings that would not otherwise be identified. For example, the cost of source-zone excavation or construction of a permeable reactive barrier at X-701B might be substantially reduced if contaminated soil could be buried on site at an existing or planned landfill. This allowance would improve the feasibility and competitiveness of both remedies. A comprehensive examination of ongoing and future environmental activities across the Portsmouth Gaseous Diffusion Plant is necessary to optimize the selection and timing of X-701B remediation with respect to cleanup efficiency, safety, and economics. A selected group of technical experts attended the technical workshop at the Portsmouth Gaseous Diffusion Plant from November 18 through 21, 2008. During the first day of the workshop, both contractor and DOE site personnel briefed the workshop participants and took them on a tour of the X-701B site. The initial briefing was attended by representatives of Ohio EPA who participated in the discussions. On subsequent days, the team reviewed baseline data and reports, were provided additional technical information from site personnel, evaluated work plans, determined critical issues and uncertainties, and recommended alternatives. This report documents the findings and recommendations of the independent technical review team.« less

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

Investigational hormone receptor agonists as ongoing female contraception: a focus on selective progesterone receptor modulators in early clinical development.

PubMed

Nelson, Anita L

2015-01-01

As efforts are made to continue to increase the safety of contraceptive methods, those without estrogen have attracted new attention. Progestin-only options are available in many delivery systems, but most cause disturbed bleeding patterns. For gynecologic patients, selective progesterone receptor modulators (SPRMs) have been approved for medical abortion, for ovulation suppression in emergency contraception, and for the treatment of heavy menstrual bleeding due to leiomyoma. This article discusses the role of SPRMs in controlling fertility on an ongoing basis with particular emphasis on mifepristone and ulipristal acetate (UPA), since none of the other compounds has progressed out of early Phase I - II testing. It also discusses important information about the mechanisms of action and safety of these two SPRMs. Of all the investigational hormone agonist/antagonists, SPRMs have demonstrated the greatest potential as ongoing female contraceptives. They have the ability to suppress ovulation after initiation of the luteinizing hormone (LH) surge without affecting ovarian production of estrogen or inducing any significant metabolic changes. SPRMs may well be able to provide longer term contraception as oral agents, vaginal rings, and perhaps even intrauterine devices. UPA has the greatest promise. Current research needs to be expanded.

Antimalarial compounds in Phase II clinical development.

PubMed

Held, Jana; Jeyaraj, Sankarganesh; Kreidenweiss, Andrea

2015-03-01

Malaria is a major health problem in endemic countries and chemotherapy remains the most important tool in combating it. Treatment options are limited and essentially rely on a single drug class - the artemisinins. Efforts are ongoing to restrict the evolving threat of artemisinin resistance but declining sensitivity has been reported. Fueled by the ambitious aim of malaria eradication, novel antimalarial compounds, with improved properties, are now in the progressive phase of drug development. Herein, the authors describe antimalarial compounds currently in Phase II clinical development and present the results of these investigations. Thanks to recent efforts, a number of promising antimalarial compounds are now in the pipeline. First safety data have been generated for all of these candidates, although their efficacy as antimalarials is still unclear for most of them. Of particular note are KAE609, KAF156 and DSM265, which are of chemical scaffolds new to malaria chemotherapy and would truly diversify antimalarial options. Apart from SAR97276, which also has a novel chemical scaffold that has had its development stopped, all other compounds in the pipeline belong to already known substance classes, which have been chemically modified. At this moment in time, there is not one standout compound that will revolutionize malaria treatment but several compounds that will add to its control in the future.

Tau-Centric Targets and Drugs in Clinical Development for the Treatment of Alzheimer's Disease

PubMed Central

Solfrizzi, Vincenzo; Imbimbo, Bruno P.; Lozupone, Madia; Santamato, Andrea; Zecca, Chiara; Barulli, Maria Rosaria; Bellomo, Antonello; Pilotto, Alberto; Daniele, Antonio; Greco, Antonio

2016-01-01

The failure of several Phase II/III clinical trials in Alzheimer's disease (AD) with drugs targeting β-amyloid accumulation in the brain fuelled an increasing interest in alternative treatments against tau pathology, including approaches targeting tau phosphatases/kinases, active and passive immunization, and anti-tau aggregation. The most advanced tau aggregation inhibitor (TAI) is methylthioninium (MT), a drug existing in equilibrium between a reduced (leuco-methylthioninium) and oxidized form (MT+). MT chloride (methylene blue) was investigated in a 24-week Phase II clinical trial in 321 patients with mild to moderate AD that failed to show significant positive effects in mild AD patients, although long-term observations (50 weeks) and biomarker studies suggested possible benefit. The dose of 138 mg/day showed potential benefits on cognitive performance of moderately affected AD patients and cerebral blood flow in mildly affected patients. Further clinical evidence will come from the large ongoing Phase III trials for the treatment of AD and the behavioral variant of frontotemporal dementia on a new form of this TAI, more bioavailable and less toxic at higher doses, called TRx0237. More recently, inhibitors of tau acetylation are being actively pursued based on impressive results in animal studies obtained by salsalate, a clinically used derivative of salicylic acid. PMID:27429978

Safinamide: FCE 26743, NW 1015, PNU 151774, PNU 151774E.

PubMed

2004-01-01

Safinamide [NW 1015, PNU 151774E; FCE 26743] is a potent anticonvulsant and antiparkinsonian compound that is being developed by Newron Pharmaceuticals in Europe. It has been shown to antagonise the calcium and sodium channels, as well as inhibit monoamine oxidase type-B (MAO-B). Phase III trials for the treatment of Parkinson's disease are underway in Germany and Europe, while phase II trials in patients with epilepsy are ongoing in Italy. Newron Pharmaceuticals was founded at the end of 1998 after Pharmacia & Upjohn announced its worldwide restructuring programme. Newron obtained the rights to safinamide, which Pharmacia Corporation (now Pfizer) had been developing as PNU 151774E. Safinamide was originated by Farmitalia-CarloErba in Italy. Newron now owns all intellectual property associated with the drug.A multinational phase II trial for Parkinson's disease in Europe has shown positive results in slowing the progression of the disease; however, due to the placebo-effect seen in this study, a longer (6-month) phase IIb study is planned for the second quarter of 2003. In July 2003, Newron received an IND from the US FDA authorising a phase I trial to confirm that no dietary restrictions are needed in patients while being treated with safinamide. This study is be conducted in 12 healthy volunteers at the University of Vienna, Austria, and will be followed by efficacy studies in Parkinson's disease in the US. Five phase I trials were completed in April 2001 in Switzerland. Safinamide combines sodium and calcium channel modulatory activity with monoamine oxidase B inhibition.

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.

Improving practice in community-based settings: a randomized trial of supervision - study protocol.

PubMed

Dorsey, Shannon; Pullmann, Michael D; Deblinger, Esther; Berliner, Lucy; Kerns, Suzanne E; Thompson, Kelly; Unützer, Jürgen; Weisz, John R; Garland, Ann F

2013-08-10

Evidence-based treatments for child mental health problems are not consistently available in public mental health settings. Expanding availability requires workforce training. However, research has demonstrated that training alone is not sufficient for changing provider behavior, suggesting that ongoing intervention-specific supervision or consultation is required. Supervision is notably under-investigated, particularly as provided in public mental health. The degree to which supervision in this setting includes 'gold standard' supervision elements from efficacy trials (e.g., session review, model fidelity, outcome monitoring, skill-building) is unknown. The current federally-funded investigation leverages the Washington State Trauma-focused Cognitive Behavioral Therapy Initiative to describe usual supervision practices and test the impact of systematic implementation of gold standard supervision strategies on treatment fidelity and clinical outcomes. The study has two phases. We will conduct an initial descriptive study (Phase I) of supervision practices within public mental health in Washington State followed by a randomized controlled trial of gold standard supervision strategies (Phase II), with randomization at the clinician level (i.e., supervisors provide both conditions). Study participants will be 35 supervisors and 130 clinicians in community mental health centers. We will enroll one child per clinician in Phase I (N = 130) and three children per clinician in Phase II (N = 390). We use a multi-level mixed within- and between-subjects longitudinal design. Audio recordings of supervision and therapy sessions will be collected and coded throughout both phases. Child outcome data will be collected at the beginning of treatment and at three and six months into treatment. This study will provide insight into how supervisors can optimally support clinicians delivering evidence-based treatments. Phase I will provide descriptive information, currently unavailable in the literature, about commonly used supervision strategies in community mental health. The Phase II randomized controlled trial of gold standard supervision strategies is, to our knowledge, the first experimental study of gold standard supervision strategies in community mental health and will yield needed information about how to leverage supervision to improve clinician fidelity and client outcomes. ClinicalTrials.gov NCT01800266.

Improving practice in community-based settings: a randomized trial of supervision – study protocol

PubMed Central

2013-01-01

Background Evidence-based treatments for child mental health problems are not consistently available in public mental health settings. Expanding availability requires workforce training. However, research has demonstrated that training alone is not sufficient for changing provider behavior, suggesting that ongoing intervention-specific supervision or consultation is required. Supervision is notably under-investigated, particularly as provided in public mental health. The degree to which supervision in this setting includes ‘gold standard’ supervision elements from efficacy trials (e.g., session review, model fidelity, outcome monitoring, skill-building) is unknown. The current federally-funded investigation leverages the Washington State Trauma-focused Cognitive Behavioral Therapy Initiative to describe usual supervision practices and test the impact of systematic implementation of gold standard supervision strategies on treatment fidelity and clinical outcomes. Methods/Design The study has two phases. We will conduct an initial descriptive study (Phase I) of supervision practices within public mental health in Washington State followed by a randomized controlled trial of gold standard supervision strategies (Phase II), with randomization at the clinician level (i.e., supervisors provide both conditions). Study participants will be 35 supervisors and 130 clinicians in community mental health centers. We will enroll one child per clinician in Phase I (N = 130) and three children per clinician in Phase II (N = 390). We use a multi-level mixed within- and between-subjects longitudinal design. Audio recordings of supervision and therapy sessions will be collected and coded throughout both phases. Child outcome data will be collected at the beginning of treatment and at three and six months into treatment. Discussion This study will provide insight into how supervisors can optimally support clinicians delivering evidence-based treatments. Phase I will provide descriptive information, currently unavailable in the literature, about commonly used supervision strategies in community mental health. The Phase II randomized controlled trial of gold standard supervision strategies is, to our knowledge, the first experimental study of gold standard supervision strategies in community mental health and will yield needed information about how to leverage supervision to improve clinician fidelity and client outcomes. Trial registration ClinicalTrials.gov NCT01800266 PMID:23937766

[Clinical Tests Testing New Therapies for Stargardt Disease].

PubMed

Kousal, B; Ďuďáková, Ľ; Hlavatá, L; Lišková, P

2016-02-01

To provide information on currently ongoing clinical trials for Stargardt disease. We have searched the clinical trial register (www.clinicaltrials.gov) for the keyword "Stargardt" and list active ongoing studies. There are currently eight registered clinical trials enrolling patients with Stargardt disease; all in phase I or II aiming at four mechanisms of action: inhibition of the production of vitamin A toxic dimers, gene therapy restoring wild type transcription of the ABCA4 gene, neuroprotection preventing retinal cells from oxidative damage, and replacement of the damaged retinal pigment epithelium using stem cell therapy. The basic prerequisite for enrolment in the vast majority of clinical trials is confirmation of the clinical diagnosis by mutational analysis. The wide variety of therapies that are registered as clinical trials for Stargardt disease significantly raises the possibility that effective treatments will be available in the near future for this currently incurable condition and that molecular genetic testing should be increasingly considered. Stargardt disease, clinical trial, ABCA4, mutation.

Constraints on Martian Aerosol Particles Using MGS/TES and HST Data: Shapes

NASA Astrophysics Data System (ADS)

Wolff, M. J.; Clancy, R. T.; Pitman, K. M.; Bell, J. F.; James, P. B.

2001-12-01

In order to constrain the shape of water ice and dust aerosols, we have combined a numerical approach for axisymmetric particle shapes, i.e., cylinders, disks, spheroids (Waterman's T-Matrix approach as improved by Mishchenko and collaborators; cf., Mishchenko et al. 1997, JGR, 102, D14, 16,831), with a multiple-scattering radiative transfer algorithm. We utilize a two-stage iterative process. First, we empirically derive a scattering phase function for each aerosol component from radiative transfer models of Mars Global Surveyor Thermal Emission Spectrometer Emission Phase Function (EPF) sequences. Next, we perform a series of scattering calculations, adjusting our parameters to arrive at a ``best-fit'' theoretical phase function. It is important to note that in addition to randomly-oriented particles, we explicitly consider the possibility of (partially) aligned aerosol particles as well. Thus far, we have been analyzing the three empirically-derived presented by Clancy et al. (this meeting): dust, Type I ice particles (effective radii ~ 1-2 microns), and Type II ice particles (effective radii ~ 3-4 microns). We find that the ``dust'' phase function is best fit by randomly-oriented cylinders with an axial ratio (D/L = diameter-to-length) of either 2.3 or 0.6. Similarly, the shape of the Type II ice curve is reasonably reproduced by randomly-oriented spheroids with an axial ratio of either 0.7 or 1.4. However, neither of the two shapes (nor that of spheres or randomly-oriented hexagonal prisms) can reproduce the phase function derived for the Type I ice. This led to the direct consideration of oriented or aligned particles. which, at least qualitatively, have the ability to account for the phase function shapes for both Type I and II ice particles. The difference between these two phase functions may represent the degree of alignment, with the Type II particles being much less-aligned. The calculations for partially aligned particles is quite numerically intensive and this avenue of research is currently in progress. Additional work is also being done to further constrain the dust aerosol properties using both TES visible/IR and Hubble Space Telescope UV-NIR spectroscopy/imaging data of the recent (and ongoing) Martian global dust storm. Our work has been supported through NASA (MDAP) grant NAG5-9820, (MED) JPL contract 961471, STScI GO programs #8577 and #9052.

Novel drugs in clinical development for hepatocellular carcinoma.

PubMed

Waidmann, Oliver; Trojan, Jörg

2015-01-01

Sorafenib is the only systemic drug approved for the treatment of advanced hepatocellular carcinoma (HCC). Within recent years, several investigational agents mainly targeting angiogenesis failed in late-phase clinical development either due to toxicity or lack of benefit. This review covers recent clinical data on systemic agents and ongoing trials in patients with advanced HCC. In unselected patients with advanced HCC, disappointing results have been reported from several large trials. However, in two subgroups encouraging results have been achieved. Treatment with the MET inhibitor tivantinib resulted in a substantial survival benefit in the subgroup of MET overexpressing tumors in a randomized Phase II trial. Furthermore, the vascular endothelial growth factor receptor 2 antibody ramucirumab resulted in improved overall survival in patients with baseline α-fetoprotein (AFP) ≥ 400 ng/ml in a Phase III trial. These two agents, and several others, will be further developed in HCC. Moreover, immunotherapeutics such as checkpoint inhibitors, programmed death receptor-1 blocking antibodies and oncolytic viruses are under investigation in advanced HCC.

Structural and functional aspects of social support as predictors of mental and physical health trajectories: Whitehall II cohort study.

PubMed

Hakulinen, Christian; Pulkki-Råback, Laura; Jokela, Markus; E Ferrie, Jane; Aalto, Anna-Mari; Virtanen, Marianna; Kivimäki, Mika; Vahtera, Jussi; Elovainio, Marko

2016-07-01

Social support is associated with better health. However, only a limited number of studies have examined the association of social support with health from the adult life course perspective and whether this association is bidirectional. Participants (n=6797; 30% women; age range from 40 to 77 years) who were followed from 1989 (phase 2) to 2006 (phase 8) were selected from the ongoing Whitehall II Study. Structural and functional social support was measured at follow-up phases 2, 5 and 7. Mental and physical health was measured at five consecutive follow-up phases (3-8). Social support predicted better mental health, and certain functional aspects of social support, such as higher practical support and higher levels of negative aspects in social relationships, predicted poorer physical health. The association between negative aspects of close relationships and physical health was found to strengthen over the adult life course. In women, the association between marital status and mental health weakened until the age of approximately 60 years. Better mental and physical health was associated with higher future social support. The strength of the association between social support and health may vary over the adult life course. The association with health seems to be bidirectional. 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/

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

PubMed

Korn, Edward L; Freidlin, Boris

2017-06-01

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

Satraplatin: BMS 182751, BMY 45594, JM 216.

PubMed

2007-01-01

Satraplatin [BMS 182751, BMY 45594, JM 216] belongs to a series of orally-active platinum compounds with anticancer activity. It was jointly originated by Bristol-Myers Squibb, Johnson Matthey and the Institute of Cancer Research in the UK; however, Johnson Matthey has since ceased involvement with drug development. Subsequently, the agent has been licensed to and is under development with GPC Biotech, Pharmion and Spectrum Pharmaceuticals. Clinical trials are underway to evaluate satraplatin among patients with different tumour types, including prostate, breast, cervical and lung cancers. The compound is under regulatory review with the US FDA for the treatment of hormone-refractory prostate cancer. NeoTherapeutics (now Spectrum Pharmaceuticals) granted GPC Biotech an exclusive worldwide licence to develop and market satraplatin in October 2002. Under the terms of the agreement, GPC Biotech is fully funding development costs and commercialisation requirements for the drug. The deal also involves GPC Biotech paying a signing fee, milestone and royalty payments. Spectrum is a member of a joint development committee headed by GPC Biotech to govern development of satraplatin. Previously in October 2001, NeoOncoRx (Spectrum Pharmaceuticals) gained the rights to develop and market the compound worldwide. In December 2005, GPC Biotech and Pharmion Corporation entered into a co-development and license agreement for satraplatin. Under the agreement terms, Pharmion has exclusive commercialisation rights for Europe, Turkey, the Middle East, Australia and New Zealand, while GPC Biotech retains rights to North America and all other territories. Pharmion made an upfront payment of $US37.1 million to GPC Biotech, which included reimbursement for past clinical development costs plus funding for ongoing and certain clinical development activities to be jointly conducted by the companies. In addition, both parties will pursue a joint development plan for satraplatin in a variety of tumour types and will share global development costs, for which Pharmion has made an additional commitment of $US22.2 million. GPC Biotech could also receive up to $US270 million in milestone payments and royalties on sales. Both companies will manage regulatory and commercial activities in their respective territories. A registrational phase III study is ongoing among 950 patients with HRPC. This global, multicentre, randomised study, called SPARC (Satraplatin and Prednisone Against Refractory Cancer), is assessing satraplatin plus prednisone versus prednisone alone as second-line therapy in HRPC patients. Top-line results from the trial showed that patients who received satraplatin plus prednisone had a 40% reduction in the risk of progression compared with patients who received prednisone plus placebo. In accordance with the recommendation of the independent Data Monitoring Board for the SPARC trial, patients who have not progressed will continue to be treated and all patients will be followed for overall survival. The company expects to have final overall survival results in the fall of 2007. The company intends to complete the NDA filing with the FDA before the end of 2006. In February 2006, GPC Biotech raised euro36.2 million from a private placement of shares; the funds will be used in the commercialisation of satraplatin in the US. GBC Biotech received a Scientific Advice letter from the EMEA in January 2004, enabling the company to use the SPARC trial for registrational plans in both Europe and the US. Data from the pivotal phase III trial are expected in the second half of 2006. If positive, the findings will form the basis of a MAA filing with the EMEA for satraplatin as a second-line therapy of HRPC. The EMEA has confirmed that it would accept the final analysis for progression-free survival (PFS) from the SPARC trial and the available overall survival data as the basis for the MAA submission expected in the first quarter of 2007. In December 2005, enrolment started for a phase II study of satraplatin plus paclitaxel as a first-line treatment for unresectable advanced NSCLC. This open-label study is enrolling up to 40 patients at sites in the US. In addition, GPC Biotech and Spectrum have initiated a phase I/II trial of satraplatin plus radiation therapy among patients with NSCLC. The study is expected to enrol up to 30 patients in the phase I portion to determine dose-limiting toxicities and maximum tolerated doses. Once these are established, the phase II portion will enrol patients to evaluate efficacy and safety. This trial is expected to be closely followed by phase I/II trials of satraplatin in combination with docetaxel and paclitaxel. GPC Biotech initiated a phase I trial in July 2005 investigating satraplatin plus docetaxel among patients with advanced solid tumours in the US. The study is primarily focused on establishing the toxicity and maximum tolerated doses of combination therapy to determine suitable dosages for phase II trials. Enrolment is ongoing for the open-label, single-centre study with a target of up to 48 patients. A phase I study is evaluating satraplatin in combination with gemcitabine in patients with advanced solid tumours. Previously, Bristol-Myers Squibb initiated phase III development of satraplatin in Europe and the US in 1996. The trials were being conducted in patients with ovarian, non-small cell lung and small-cell lung cancers. However, the company closed all ongoing trials of satraplatin in 1999. Satraplatin is protected by a number of patents issued in the US, EU, Japan, Canada and Australia. The patents have been assigned to Johnson Matthey, a multinational chemical company in the UK, which has exclusively sub-licensed these to GPC Biotech under a co-development and licensing agreement with Spectrum Pharmaceuticals. The patents cover the composition of matter and anticancer uses of various platinum-based compounds, including satraplatin. Two of the US patents will expire in 2008 and 2010, respectively, while patents in most other countries will expire in 2009.

Emerging drugs for neuropathic pain.

PubMed

Gilron, Ian; Dickenson, Anthony H

2014-09-01

Neuropathic pain is a costly and disabling condition, which affects up to 8% of the population. Available therapies often provide incomplete pain relief and treatment-related side effects are common. Preclinical neuropathic pain models have facilitated identification of several promising targets, which have progressed to human clinical phases of evaluation. A systematic database search yielded 25 new molecular entities with specified pharmacological mechanisms that have reached Phase II or III clinical trials. These include calcium channel antagonists, vanilloid receptor antagonists, potassium channel agonists, NMDA antagonists, novel opioid receptor agonists, histamine H3 receptor antagonists, a novel sodium channel antagonist, serotonin modulators, a novel acetylcholine receptor agonist, α-2b adrenoreceptor agonist, cannabinoid CB2 receptor agonist, nitric oxide synthase inhibitor, orexin receptor antagonist, angiotensin II 2 antagonist, imidazoline I2 receptor agonist, apoptosis inhibitor and fatty acid amide hydrolase inhibitor. Although the diversity of pharmacological mechanisms of interest emphasise the complexity of neuropathic pain transmission, the considerable number of agents under development reflect a continued enthusiasm in drug development for neuropathic pain. Ongoing enhancements in methodology of both preclinical and clinical research and closer translation in both directions are expected to more efficiently identify new agents, which will improve the management of neuropathic pain.

Applying neurobiology to the treatment of adults with anorexia nervosa.

PubMed

Hill, Laura; Peck, Stephanie Knatz; Wierenga, Christina E; Kaye, Walter H

2016-01-01

Anorexia nervosa is a severe, biologically based brain disorder with significant medical complications. It is critical that new, effective treatments are developed to interrupt the persistent course of the illness due to the medical and psychological sequelae. Several psychosocial, behavioral and pharmacologic interventions have been investigated in adult anorexia nervosa; however, evidence shows that their impact is weak and treatment effects are generally small. This paper describes a new neurobiological anorexia nervosa model that shifts focus from solely external influences, such as social and family, to include internal influences that integrate genetic and neurobiological contributions, across the age span. The model serves as a theoretical structure for a new, five-day treatment, outlined in this paper, targeting anorexia nervosa temperament, which integrates neurobiological dimensions into evidence-based treatment interventions. The treatment is in two phases. Phase I is a five day, 40 hour treatment for anorexia nervosa adults. Phase II is the follow-up and is currently being developed. Preliminary qualitative acceptability data on 37 adults with anorexia nervosa and 60 supports (e.g., spouses, parents, aunts, friends, partners, children of anorexia nervosa adults) are promising from Phase I. Clients with anorexia nervosa and their supports report that learning neurobiological facts improved their understanding of the illness and helped equip them with better tools to manage anorexia nervosa traits and symptoms. In addition, nutritional knowledge changed significantly. This is the first neurobiologically based, five-day treatment for adults with anorexia nervosa and their supports. It is a new model that outlines underlying genetic and neurobiological contributions to anorexia nervosa that serves as a foundation to treat both traits and symptoms. Preliminary qualitative findings are promising, with both clients and supports reporting that the neurobiological treatment approach helped them better understand the illness, while better conceptualizing how to respond to their traits and manage their symptoms. Data in Phase I shows promise as a neurobiologically based intervention for anorexia nervosa, and it serves as a foundation for the development of Phase II. Evidence of ongoing program efficacy will be described as data are reported on Phase II. NCT NCT02852538 Registered 1 August 2016.

The Recombinant Bacille Calmette-Guérin Vaccine VPM1002: Ready for Clinical Efficacy Testing.

PubMed

Nieuwenhuizen, Natalie E; Kulkarni, Prasad S; Shaligram, Umesh; Cotton, Mark F; Rentsch, Cyrill A; Eisele, Bernd; Grode, Leander; Kaufmann, Stefan H E

2017-01-01

The only licensed vaccine against tuberculosis (TB), bacille Calmette-Guérin (BCG), protects against severe extrapulmonary forms of TB but is virtually ineffective against the most prevalent form of the disease, pulmonary TB. BCG was genetically modified at the Max Planck Institute for Infection Biology to improve its immunogenicity by replacing the urease C encoding gene with the listeriolysin encoding gene from Listeria monocytogenes . Listeriolysin perturbates the phagosomal membrane at acidic pH. Urease C is involved in neutralization of the phagosome harboring BCG. Its depletion allows for rapid phagosome acidification and promotes phagolysosome fusion. As a result, BCGΔ ureC :: hly (VPM1002) promotes apoptosis and autophagy and facilitates release of mycobacterial antigens into the cytosol. In preclinical studies, VPM1002 has been far more efficacious and safer than BCG. The vaccine was licensed to Vakzine Projekt Management and later sublicensed to the Serum Institute of India Pvt. Ltd., the largest vaccine producer in the world. The vaccine has passed phase I clinical trials in Germany and South Africa, demonstrating its safety and immunogenicity in young adults. It was also successfully tested in a phase IIa randomized clinical trial in healthy South African newborns and is currently undergoing a phase IIb study in HIV exposed and unexposed newborns. A phase II/III clinical trial will commence in India in 2017 to assess efficacy against recurrence of TB. The target indications for VPM1002 are newborn immunization to prevent TB as well as post-exposure immunization in adults to prevent TB recurrence. In addition, a Phase I trial in non-muscle invasive bladder cancer patients has been completed, and phase II trials are ongoing. This review describes the development of VPM1002 from the drawing board to its clinical assessment.

Interleukin-21: updated review of Phase I and II clinical trials in metastatic renal cell carcinoma, metastatic melanoma and relapsed/refractory indolent non-Hodgkin's lymphoma.

PubMed

Hashmi, Mehmood H; Van Veldhuizen, Peter J

2010-05-01

In advanced renal cell cancer and malignant melanoma, the current FDA approved immune modulators, such as IL-2, are the only agents which provide a durable complete remission. These responses, however, occur in < 10% of treated patients and their applicability is limited to selected patients because of their toxicity. The identification of new immunotherapeutic agents with an improved response rate and toxicity profile would represent a significant advancement in the treatment of these malignancies. This is a comprehensive review of IL-21 including its pharmacology and current developmental status. A literature review was performed using all PubMed listed publications involving IL-21, including original research articles, reviews and abstracts. It also includes a review of current ongoing trials and information from the official product website. Recombinant IL-21 (rIL-21) is a new immune modulator currently undergoing Phase I and II testing. It is a cytokine with a four helix structure that has structural and sequence homology to IL-2 and -15, but also possesses many unique biological properties. In this review, we evaluate the development, pharmacologic properties, safety profile and current clinical efficacy of rIL-21. rIL-21 has an acceptable safety profile and encouraging single agent activity in early phase renal cell carcinoma and melanoma clinical trials.

Clinical and biochemical studies support smokeless tobacco’s carcinogenic potential in the human oral cavity

PubMed Central

Mallery, Susan R.; Tong, Meng; Michaels, Gregory C.; Kiyani, Amber R.; Hecht, Stephen S.

2014-01-01

In 2007, International Agency for Cancer Research presented compelling evidence that linked smokeless tobacco use to the development of human oral cancer. While these findings imply vigorous local carcinogen metabolism, little is known regarding levels and distribution of Phase I, II and drug egress enzymes in human oral mucosa. In the study presented here, we integrated clinical data, imaging and histopathologic analyses of an oral squamous cell carcinoma that arose at the site of smokeless tobacco quid placement in a patient. Immunoblot and immunohistochemical (IHC) analyses were employed to identify tumor and normal human oral mucosal smokeless tobacco-associated metabolic activation and detoxification enzymes. Human oral epithelium contains every known Phase I enzyme associated with nitrosamine oxidative bioactivation with ~2 fold inter-donor differences in protein levels. Previous studies have confirmed ~3.5 fold inter-donor variations in intraepithelial Phase II enzymes. Unlike the superficially located enzymes in non-replicating esophageal surface epithelium, IHC studies confirmed oral mucosal nitrosamine metabolizing enzymes reside in the basilar and suprabasilar region which notably is the site of ongoing keratinocyte DNA replication. Clearly, variations in product composition, nitrosamine metabolism and exposure duration will modulate clinical outcomes. The data presented here form a coherent picture consistent with the abundant experimental data that links tobacco-specific nitrosamines to human oral cancer. PMID:24265177

Review of the contemporary cytotoxic and biologic combinations available for the treatment of metastatic breast cancer.

PubMed

Tkaczuk, Katherine H Rak

2009-01-01

Treatment of metastatic breast cancer (MBC) with > or =2 chemotherapeutic agents concurrently has been shown to increase response rates, often at the cost of a substantial increase in toxicity, and with minimal impact on the overall survival. However, some combinations of the newer cytotoxic agents, as well as combinations of chemotherapeutic agents and targeted biologic anticancer agents, can produce synergistic efficacy with a manageable toxicity profile. The aims of this work were to provide an overview of the currently approved combination regimens available for the treatment of MBC and to consider the clinical data supporting other drug combinations that may supplement the current therapeutic choices in the near future. Literature searches were performed using MEDLINE/PubMed, with a focus on combination therapies for the treatment of MBC that are approved by the US Food and Drug Administration (FDA) or in Phase III clinical trials. The National Institutes of Health's Clinical Trial Registry was searched for relevant ongoing clinical trials in specific areas. Bibliographies were also searched for additional relevant material. Preference was given to recently published, larger, well-designed clinical trials that influence current prescribing practices. Phase I and II studies, and/or studies older than 10 years (ie, published earlier than 1999), were afforded less emphasis or were disregarded. Combinations of taxanes with capecitabine or gemcitabine, and ixabepilone plus capecitabine, are approved by the FDA as combination regimens for the treatment of MBC. The use of targeted therapies such as trastuzumab, bevacizumab, or lapatinib in combination with taxanes (for the former two) or capecitabine (for lapatinib) is also approved. Several investigational drug combinations are also currently undergoing evaluation in clinical trials, including combinations of bevacizumab and gemcitabine with capecitabine or alternative taxanes. Although results from Phase I and II studies are largely encouraging so far, the data from ongoing Phase III studies will ultimately dictate changes in clinical practice. It seems unlikely that any single agent or combination regimen will emerge as superior in all patients with MBC, given the heterogeneous nature of the disease and patient population. New combination regimens for MBC may broaden the range of treatment options currently available to delay disease progression for as long as possible. Copyright 2009 Excerpta Medica Inc. All rights reserved.

Investigational drugs for coagulation disorders.

PubMed

Mannucci, Pier Mannuccio; Mancuso, Maria Elisa

2013-08-01

The current standard treatment in persons with hemophilia (PWH) is prophylaxis, given intravenously twice or thrice weekly, which is associated with a non negligible burden on patients' quality of life. Therefore the main attempts aiming to improve the management of PWH are targeted towards the development of a new generation of coagulation factors endowed with properties facilitating prophylaxis and/or a better control of bleeding. This article summarizes the main results obtained so far in the development of new antihemophilic products, and emphasizes the formidable requirements imposed upon by regulatory agencies to get marketing authorization for new drugs, which make progress in this field difficult. Published literature on new molecules for replacement treatment in hemophilia A and B has been retrieved by using PubMed search and all ongoing clinical trials have been looked for online. New molecules are usually engineered to have a longer plasma half-life but also in some instances a higher potency. The prolongation of half-life may be obtained by using sustained release delivery vehicles, by chemical modification or by creating fusion proteins. Factors VIII, IX and VII have been variably modified in order to obtain improved coagulation products and results from Phase I/II studies are encouraging, particularly for factor IX. However, Phase III studies that should provide evidence on efficacy and effectiveness more cogent for clinical use are still ongoing and results are not yet available.

The complete genome sequence of Lactobacillus bulgaricus reveals extensive and ongoing reductive evolution.

PubMed

van de Guchte, M; Penaud, S; Grimaldi, C; Barbe, V; Bryson, K; Nicolas, P; Robert, C; Oztas, S; Mangenot, S; Couloux, A; Loux, V; Dervyn, R; Bossy, R; Bolotin, A; Batto, J-M; Walunas, T; Gibrat, J-F; Bessières, P; Weissenbach, J; Ehrlich, S D; Maguin, E

2006-06-13

Lactobacillus delbrueckii ssp. bulgaricus (L. bulgaricus) is a representative of the group of lactic acid-producing bacteria, mainly known for its worldwide application in yogurt production. The genome sequence of this bacterium has been determined and shows the signs of ongoing specialization, with a substantial number of pseudogenes and incomplete metabolic pathways and relatively few regulatory functions. Several unique features of the L. bulgaricus genome support the hypothesis that the genome is in a phase of rapid evolution. (i) Exceptionally high numbers of rRNA and tRNA genes with regard to genome size may indicate that the L. bulgaricus genome has known a recent phase of important size reduction, in agreement with the observed high frequency of gene inactivation and elimination; (ii) a much higher GC content at codon position 3 than expected on the basis of the overall GC content suggests that the composition of the genome is evolving toward a higher GC content; and (iii) the presence of a 47.5-kbp inverted repeat in the replication termination region, an extremely rare feature in bacterial genomes, may be interpreted as a transient stage in genome evolution. The results indicate the adaptation of L. bulgaricus from a plant-associated habitat to the stable protein and lactose-rich milk environment through the loss of superfluous functions and protocooperation with Streptococcus thermophilus.

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

PubMed

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

2015-12-22

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

Creep of water ices at planetary conditions: A compilation

USGS Publications Warehouse

Durham, W.B.; Kirby, S.H.; Stern, L.A.

1997-01-01

Many constitutive laws for the flow of ice have been published since the advent of the Voyager explorations of the outer solar system. Conflicting data have occasionally come from different laboratories, and refinement of experimental techniques has led to the publication of laws that supersede earlier ones. In addition, there are unpublished data from ongoing research that also amend the constitutive laws. Here we compile the most current laboratory-derived flow laws for water ice phases I, II, III, V, and VI, and ice I mixtures with hard particulates. The rheology of interest is mainly that of steady state, and the conditions reviewed are the pressures and temperatures applicable to the surfaces and interiors of icy moons of the outer solar system. Advances in grain-size-dependent creep in ices I and II as well as in phase transformations and metastability under differential stress are also included in this compilation. At laboratory strain rates the several ice polymorphs are rheologically distinct in terms of their stress, temperature, and pressure dependencies but, with the exception of ice III, have fairly similar strengths. Hard particulates strengthen ice I significantly only at high particulate volume fractions. Ice III has the potential for significantly affecting mantle dynamics because it is much weaker than the other polymorphs and its region of stability, which may extend metastably well into what is nominally the ice II field, is located near likely geotherms of large icy moons. Copyright 1997 by the American Geophysical Union.

Phase II study of the safety and antitumor activity of the hypoxia-activated prodrug TH-302 in combination with doxorubicin in patients with advanced soft tissue sarcoma.

PubMed

Chawla, Sant P; Cranmer, Lee D; Van Tine, Brian A; Reed, Damon R; Okuno, Scott H; Butrynski, James E; Adkins, Douglas R; Hendifar, Andrew E; Kroll, Stew; Ganjoo, Kristen N

2014-10-10

TH-302, a prodrug of the cytotoxic alkylating agent bromo-isophosphoramide mustard, is preferentially activated in hypoxic conditions. This phase II study investigated TH-302 in combination with doxorubicin, followed by single-agent TH-302 maintenance therapy in patients with first-line advanced soft tissue sarcoma (STS) to assess progression-free survival (PFS), response rate, overall survival, safety, and tolerability. In this open-label phase II study, TH-302 300 mg/m(2) was administered intravenously on days 1 and 8 with doxorubicin 75 mg/m(2) on day 1 of each 21-day cycle. After six cycles, patients with stable and/or responding disease could receive maintenance monotherapy with TH-302. Ninety-one patients initiated TH-302 plus doxorubicin induction treatment. The PFS rate at 6 months (primary efficacy measure) was 58% (95% CI, 46% to 68%). Median PFS was 6.5 months (95% CI, 5.8 to 7.7 months); median overall survival was 21.5 months (95% CI, 16.0 to 26.2 months). Best tumor responses were complete response (n = 2 [2%]) and partial response (n = 30 [34%]). During TH-302 maintenance (n = 48), five patients improved from stable disease to partial response, and one patient improved from partial to complete response. The most common adverse events during induction were fatigue, nausea, and skin and/or mucosal toxicities as well as anemia, thrombocytopenia, and neutropenia. These were less severe and less frequent during maintenance. There was no evidence of TH-302-related hepatic, renal, or cardiac toxicity. PFS, overall survival, and tumor response compared favorably with historical outcomes achieved with other first-line chemotherapies for advanced STS. A phase III study of TH-302 is ongoing (NCT01440088). © 2014 by American Society of Clinical Oncology.

The Early Detection and Follow-up of the Highly Obscured Type II Supernova 2016ija/DLT16am

NASA Astrophysics Data System (ADS)

Tartaglia, L.; Sand, D. J.; Valenti, S.; Wyatt, S.; Anderson, J. P.; Arcavi, I.; Ashall, C.; Botticella, M. T.; Cartier, R.; Chen, T.-W.; Cikota, A.; Coulter, D.; Della Valle, M.; Foley, R. J.; Gal-Yam, A.; Galbany, L.; Gall, C.; Haislip, J. B.; Harmanen, J.; Hosseinzadeh, G.; Howell, D. A.; Hsiao, E. Y.; Inserra, C.; Jha, S. W.; Kankare, E.; Kilpatrick, C. D.; Kouprianov, V. V.; Kuncarayakti, H.; Maccarone, T. J.; Maguire, K.; Mattila, S.; Mazzali, P. A.; McCully, C.; Melandri, A.; Morrell, N.; Phillips, M. M.; Pignata, G.; Piro, A. L.; Prentice, S.; Reichart, D. E.; Rojas-Bravo, C.; Smartt, S. J.; Smith, K. W.; Sollerman, J.; Stritzinger, M. D.; Sullivan, M.; Taddia, F.; Young, D. R.

2018-01-01

We present our analysis of the Type II supernova DLT16am (SN 2016ija). The object was discovered during the ongoing D< 40 {Mpc} (DLT40) one-day cadence supernova search at r∼ 20.1 {mag} in the “edge-on” nearby (D=20.0+/- 4.0 {Mpc}) galaxy NGC 1532. The subsequent prompt and high-cadenced spectroscopic and photometric follow-up revealed a highly extinguished transient, with E(B-V)=1.95+/- 0.15 {mag}, consistent with a standard extinction law with R V = 3.1 and a bright ({M}V=-18.48+/- 0.77 {mag}) absolute peak magnitude. A comparison of the photometric features with those of large samples of SNe II reveals a fast rise for the derived luminosity and a relatively short plateau phase, with a slope of {S}50V=0.84+/- 0.04 {mag}/50 {days}, consistent with the photometric properties typical of those of fast-declining SNe II. Despite the large uncertainties on the distance and the extinction in the direction of DLT16am, the measured photospheric expansion velocity and the derived absolute V-band magnitude at ∼ 50 {days} after the explosion match the existing luminosity–velocity relation for SNe II. This paper includes data gathered with the 6.5 m Magellan Telescopes located at Las Campanas Observatory, Chile.

Paclitaxel and carboplatin in early phase studies: Roswell Park Cancer Institute experience in the subset of patients with lung cancer.

PubMed

Creaven, P J; Raghavan, D; Pendyala, L; Loewen, G; Kindler, H L; Berghorn, E J

1997-08-01

The combination of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) given by 3-hour infusion followed by carboplatin infused over 30 minutes has been evaluated in a series of phase I studies and is currently being explored in a phase II study in patients with limited- and extensive-stage small cell lung cancer. Pharmacokinetic measurements were performed at all dose levels in the phase I studies, in which the use of granulocyte colony-stimulating factor in previously treated patients enabled more than twice the dose of paclitaxel to be given with low to moderate doses of carboplatin (dosed to a target area under the concentration-time curve of 4.0 mg x min x mL[-1]). Treatment-naive patients tolerated high paclitaxel doses (270 mg/m2) with carboplatin (dosed to a target area under the curve of 4.5 mg x min x mL[-1]) without granulocyte colony-stimulating factor support. Twenty-three patients (including previously treated and untreated) with non-small cell lung cancer were entered at a variety of paclitaxel doses in the phase I studies. At 100 to 205 mg/m2 paclitaxel, none of nine treated patients responded; at 230 to 290 mg/m2, four (29%) of 14 responded. In the phase II study of paclitaxel 250 mg/m2 in previously untreated patients with small cell lung cancer, two of five evaluable patients with extensive-stage disease have shown a partial response. In a preliminary analysis of the pharmacodynamics of paclitaxel in relation to neurotoxicity (dose limiting in two of three phase I studies), neurotoxicity correlated with the total dose of paclitaxel, the area under the curve, and the peak paclitaxel concentration, but not with the length of time plasma paclitaxel levels remained above 0.05 micromol/L. These correlations were not strong, however, and analysis of these data is ongoing.

ASPHERICITY, INTERACTION, AND DUST IN THE TYPE II-P/II-L SUPERNOVA 2013EJ IN MESSIER 74

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

Mauerhan, Jon C.; Graham, Melissa L.; Filippenko, Alexei V.

2017-01-10

SN 2013ej is a well-studied core-collapse supernova (SN) that stemmed from a directly identified red supergiant (RSG) progenitor in galaxy M74. The source exhibits signs of substantial geometric asphericity, X-rays from persistent interaction with circumstellar material (CSM), thermal emission from warm dust, and a light curve that appears intermediate between supernovae of Types II-P and II-L. The proximity of this source motivates a close inspection of these physical characteristics and their potential interconnection. We present multiepoch spectropolarimetry of SN 2013ej during the first 107 days and deep optical spectroscopy and ultraviolet through infrared photometry past ∼800 days. SN 2013ej exhibitsmore » the strongest and most persistent continuum and line polarization ever observed for a SN of its class during the recombination phase. Modeling indicates that the data are consistent with an oblate ellipsoidal photosphere, viewed nearly edge-on and probably augmented by optical scattering from circumstellar dust. We suggest that interaction with an equatorial distribution of CSM, perhaps the result of binary evolution, is responsible for generating the photospheric asphericity. Relatedly, our late-time optical imaging and spectroscopy show that asymmetric CSM interaction is ongoing, and the morphology of broad H α emission from shock-excited ejecta provides additional evidence that the geometry of the interaction region is ellipsoidal. Alternatively, a prolate ellipsoidal geometry from an intrinsically bipolar explosion is also a plausible interpretation of the data but would probably require a ballistic jet of radioactive material capable of penetrating the hydrogen envelope early in the recombination phase. Finally, our latest space-based optical imaging confirms that the late interaction-powered light curve dropped below the stellar progenitor level, confirming the RSG star’s association with the explosion.« less

Long-acting antiviral agents for HIV treatment

PubMed Central

Margolis, David A.; Boffito, Marta

2015-01-01

Purpose of review Long-acting antiretroviral (ARV) agents are currently under development for the treatment of chronic HIV infection. This review focuses on data recently produced on injectable ARVs for patients living with HIV/AIDS and on the patients’ perspectives on the use of these agents. Recent findings Crystalline nanoparticle formulations of the nonnucleoside reverse transcriptase inhibitor rilpivirine (TMC278) and of the HIV-1 integrase strand transfer inhibitor cabotegravir (GSK1265744) have progressed into phase II clinical trials as injectable maintenance therapy for patients living with HIV/AIDS with an undetectable viral load. Summary Phase II studies evaluating the coadministration of rilpivirine and cabotegravir intramuscularly to HIV-infected individuals with an undetectable viral load are currently underway. Rilpivirine and cabotegravir are characterized by different mechanisms of action against HIV and a favorable drug interaction profile, providing a rationale for coadministration. The high potency and low daily dosing requirements of oral cabotegravir and rilpivirine facilitate long-acting formulation development. Intramuscular dosing is preceded by an oral lead-in phase to assess safety and tolerability in individual participants. In addition to assessing the safety of injectable therapies in ongoing studies, it will be important to evaluate whether differences in drug adherence between injectable and oral therapies lead to different virologic outcomes, including rates of virologic failure and the emergence of resistance. Long-acting formulations may be associated with challenges, such as the management of adverse effects with persistent drug concentrations and the risk of virologic resistance, as drug concentrations decline following discontinuation. PMID:26049949

Uterine cavity lavage: adding FISH to conventional cytogenetics for embryonic sexing and diagnosing common chromosomal aberrations.

PubMed

Ishai, D; Amiel, A; Diukman, R; Cogan, O; Lichtenstein, Z; Abramovici, H; Fejgin, M D

1995-10-01

This study was undertaken to examine the efficacy for early prenatal diagnosis of uterine cavity lavage at the level of the internal os and to assess the rate of maternal contamination. In phase I, uterine cavity lavage was performed in 38 women scheduled for pregnancy termination between 6 and 12 weeks. In addition to short- and long-term cultures, one-colour FISH (fluorescence in situ hybridization) with Y and X probes was used for fetal sexing. Two-colour FISH was used in all known male fetuses for the assessment of maternal contamination. In phase II, lavage was performed on 16 women. Fetal sex was diagnosed with direct labelled X and Y probes and common numerical chromosomal aberration was attempted with 18 and 21 direct labelled probes. Fetal sexing was successful in all cases in phases I and II. Out of 34 patients in which tissue was obtained, only FISH was done in six. Long-term cell cultures were successful in the other 28 cases, but complete karyotyping in 19 (56 per cent). No chromosomal aberration was found with the direct labelled probes 18 and 21 in FISH. Maternal contamination was assessed to be 5-10 per cent. This simple and easy-to-master technique is very effective in obtaining fetal cells early in pregnancy for genetic diagnosis, especially by FISH. However, the safety of the procedure must be tested in ongoing pregnancies.

Human papilloma virus infection in head and neck cancer.

PubMed

Tribius, Silke; Hoffmann, Markus

2013-03-01

The causal link between cervical cancer and human papilloma virus (HPV) is well known. It is now becoming clear that some types of squamous-cell carcinoma of the head and neck, particularly oropharyngeal carcinoma (OPC), are also linked to HPV infection. The development of vaccines against certain HPV genotypes has changed the management strategy for HPV-associated diseases of the uterine cervix. An analogous approach is now being considered for the prevention of HPV-associated diseases of the head and neck. We review pertinent articles retrieved by a selective search of the literature for phase II and III trials providing evidence about a possible effect of HPV status on the survival rates of patients with OPC. Seven trials fulfilled our search criteria: four phase III trials with retrospective HPV analysis and three phase II trials with retrospective and prospective HPV analysis. Patients with HPV-positive OPC survive significantly longer than those with HPV-negative OPC. Tobacco smoking has been identified as a negative prognostic factor in patients with either HPV-negative or HPV-positive disease. The established treatment strategy for OPC in patients with and without the traditional risk factors (tobacco and alcohol consumption) is now being reconsidered in the light of what we have learned about the role of HPV infection. Ongoing and projected clinical trials with risk-factor stratification may soon lead to changes in treatment. Further study is needed to answer the question whether HPV infection in the head and neck region is carcinogenic.

Intraperitoneal chemotherapy for gastric cancer with peritoneal disease: experience from Singapore and Japan.

PubMed

Kono, Koji; Yong, Wei-Peng; Okayama, Hirokazu; Shabbir, Asim; Momma, Tomoyuki; Ohki, Shinji; Takenoshita, Seiichi; So, Jimmy

2017-03-01

Among advanced gastric cancer cases, peritoneal dissemination is a life-threatening mode of metastasis, and any strategy to control peritoneal metastasis will significantly improve treatment outcomes. Since intraperitoneal administration of anticancer drugs can induce an extremely high concentration of drugs in the peritoneal cavity, intraperitoneal chemotherapy would appear to be a reasonable and promising strategy to control the peritoneal dissemination. However, it has been reported in the past that intraperitoneal administration of mitomycin C or cisplatin resulted in no significant clinical effects against peritoneal metastasis of gastric cancer. In contrast, intraperitoneal paclitaxel is expected to remain inside the peritoneal cavity due to its large molecular weight and fat solubility, leading to a high concentration of the drug in the peritoneal cavity. In fact, promising results in several phase II clinical trials using intraperitoneal paclitaxel have been reported, including a median survival time of 16.2-24.6 months and a 1-year overall survival rate of 69-78 %. Thereafter, a phase III randomized control study (PHOENIX-GC trial) with intraperitoneal paclitaxel plus systemic S-1 and intravenous paclitaxel in comparison to systemic S-1 plus cisplatin was conducted in Japan. Moreover, a phase II clinical trial of combination chemotherapy of intraperitoneal paclitaxel with systemic capecitabine plus oxaliplatin is currently ongoing in Singapore. In this review, based on clinical experience from Singapore and Japan, the clinical significance of intraperitoneal chemotherapy for gastric cancer with peritoneal disease is discussed.

Lunar Quest in Second Life, Lunar Exploration Island, Phase II

NASA Astrophysics Data System (ADS)

Ireton, F. M.; Day, B. H.; Mitchell, B.; Hsu, B. C.

2010-12-01

Linden Lab’s Second Life is a virtual 3D metaverse created by users. At any one time there may be 40,000-50,000 users on line. Users develop a persona and are seen on screen as a human figure or avatar. Avatars move through Second Life by walking, flying, or teleporting. Users form communities or groups of mutual interest such as music, computer graphics, and education. These groups communicate via e-mail, voice, and text within Second Life. Information on downloading the Second Life browser and joining can be found on the Second Life website: www.secondlife.com. This poster details Phase II in the development of Lunar Exploration Island (LEI) located in Second Life. Phase I LEI highlighted NASA’s LRO/LCROSS mission. Avatars enter LEI via teleportation arriving at a hall of flight housing interactive exhibits on the LRO/ LCROSS missions including full size models of the two spacecraft and launch vehicle. Storyboards with information about the missions interpret the exhibits while links to external websites provide further information on the mission, both spacecraft’s instrument suites, and related EPO. Other lunar related activities such as My Moon and NLSI EPO programs. A special exhibit was designed for International Observe the Moon Night activities with links to websites for further information. The sim includes several sites for meetings, a conference stage to host talks, and a screen for viewing NASATV coverage of mission and other televised events. In Phase II exhibits are updated to reflect on-going lunar exploration highlights, discoveries, and future missions. A new section of LEI has been developed to showcase NASA’s Lunar Quest program. A new exhibit hall with Lunar Quest information has been designed and is being populated with Lunar Quest information, spacecraft models (LADEE is in place) and kiosks. A two stage interactive demonstration illustrates lunar phases with static and 3-D stations. As NASA’s Lunar Quest program matures further exhibits are planned. One proposal is to develop a teacher-training program to acquaint teachers with the Lunar Quest program and to provide resources.

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.

Phase I Study of Preoperative Chemoradiation With S-1 and Oxaliplatin in Patients With Locally Advanced Resectable Rectal Cancer

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

Hong, Yong Sang; Lee, Jae-Lyun; Park, Jin Hong

Purpose: To perform a Phase I study of preoperative chemoradiation (CRT) with S-1, a novel oral fluoropyrimidine, plus oxaliplatin in patients with locally advanced rectal cancer, to determine the maximum tolerated dose and the recommended dose. Methods and Materials: Radiotherapy was delivered to a total of 45 Gy in 25 fractions and followed by a coned-down boost of 5.4 Gy in 3 fractions. Concurrent chemotherapy consisted of a fixed dose of oxaliplatin (50 mg/m{sup 2}/week) on Days 1, 8, 22, and 29 and escalated doses of S-1 on Days 1-14 and 22-35. The initial dose of S-1 was 50 mg/m{supmore » 2}/day, gradually increasing to 60, 70, and 80 mg/m{sup 2}/day. Surgery was performed within 6 {+-} 2 weeks. Results: Twelve patients were enrolled and tolerated up to Dose Level 4 (3 patients at each dose level) without dose-limiting toxicity. An additional 3 patients were enrolled at Dose Level 4, with 1 experiencing a dose-limiting toxicity of Grade 3 diarrhea. Although maximum tolerated dose was not attained, Dose Level 4 (S-1 80 mg/m{sup 2}/day) was chosen as the recommended dose for further Phase II studies. No Grade 4 toxicity was observed, and Grade 3 toxicities of leukopenia and diarrhea occurred in the same patient (1 of 15, 6.7%). Pathologic complete responses were observed in 2 of 15 patients (13.3%). Conclusions: The recommended dose of S-1 was determined to be 80 mg/m{sup 2}/day when combined with oxaliplatin in preoperative CRT, and a Phase II trial is now ongoing.« less

Zearalenone Uptake and Biotransformation in Micropropagated Triticum durum Desf. Plants: A Xenobolomic Approach.

PubMed

Rolli, Enrico; Righetti, Laura; Galaverna, Gianni; Suman, Michele; Dall'Asta, Chiara; Bruni, Renato

2018-02-14

A model was set up to elucidate the uptake, translocation, and metabolic fate of zearalenone (ZEN) in durum wheat. After treatment with ZEN, roots and shoots were profiled with LC-HRMS. A comprehensive description of in planta ZEN biotransformation and a biotechnological evaluation of the model were obtained. Up to 200 μg ZEN were removed by each plantlet after 14 days. Most ZEN and its masked forms were retained in roots, while minimal amounts were detected in leaves. Sixty-two chromatographic peaks were obtained, resulting in 7 putative phase I and 18 putative phase II metabolites. ZEN16Glc and ZEN14Glc were most abundant in roots, sulfo-conjugates and zearalenol derivatives were unable to gain systemic distribution, while distinct isomers of malonyl conjugates were found in leaves and roots. This study underlines the potential ZEN occurrence in plants without an ongoing Fusarium infection. Micropropagation may represent a tool to investigate the interplay between mycotoxins and wheat.

Progress in HIV vaccine development

PubMed Central

Hsu, Denise C.; O'Connell, Robert J.

2017-01-01

ABSTRACT An HIV-1 vaccine is needed to curtail the HIV epidemic. Only one (RV144) out of the 6 HIV-1 vaccine efficacy trials performed showed efficacy. A potential mechanism of protection is the induction of functional antibodies to V1V2 region of HIV envelope. The 2 main current approaches to the generation of protective immunity are through broadly neutralizing antibodies (bnAb) and induction of functional antibodies (non-neutralizing Abs with other potential anti-viral functions). Passive immunization using bnAb has advanced into phase II clinical trials. The induction of bnAb using mimics of the natural Env trimer or B-cell lineage vaccine design is still in pre-clinical phase. An attempt at optimization of protective functional antibodies will be assessed next with the efficacy trial (HVTN702) about to start. With on-going optimization of prime/boost strategies, the development of mosaic immunogens, replication competent vectors, and emergence of new strategies designed to induce bnAb, the prospects for a preventive HIV vaccine have never been more promising. PMID:28281871

Differential Regulation of CYP3A4 and CYP3A5 and Its Implication in Drug Discovery

PubMed Central

Lolodi, Ogheneochukome; Wang, Yue-Ming; Wright, William C.; Chen, Taosheng

2017-01-01

Cancer cells use several mechanisms to resist the cytotoxic effects of drugs, resulting in tumor progression and invasion. One such mechanism capitalizes on the body’s natural defense against xenobiotics by increasing the rate of xenobiotic efflux and metabolic inactivation. Xenobiotic metabolism typically involves conversion of parent molecules to more soluble and easily excreted derivatives in reactions catalyzed by Phase I and Phase II drug metabolizing enzymes. Recent reports indicate that components of the xenobiotic response system are upregulated in some diseases, including many cancers. Such components include the pregnane X receptor (PXR) and the cytochrome P450 (CYP) 3A4 and 3A5 enzymes. The CYP3A enzymes are a subset of the numerous enzymes that are transcriptionally activated following the interaction of PXR and many ligands. Intense research is ongoing to understand the functional ramifications of aberrant expression of these components in diseased states with the goal of designing novel drugs that can selectively target them. PMID:28558634

Small Business Innovation Research GRC Phase I, Phase II, and Post-Phase II Opportunity Assessment for 2015

NASA Technical Reports Server (NTRS)

Nguyen, Hung D.; Steele, Gynelle C.

2016-01-01

This report outlines the 2015 Small Business Innovation Research/Small Business Technology Transfer (SBIR/STTR) Phase I, Phase II, and Post-Phase II opportunity contract award results associated with NASA's Aeronautics Research Mission Directorate (ARMD), Human Exploration and Operations Mission Directorate (HEOMD), Science Mission Directorate (SMD), and Space Technology Mission Directorate (STMD) for NASA Glenn Research Center. The report also highlights the number of Phase I, Phase II, and Post-Phase II contracts awarded by mission directorate. The 2015 Phase I contract awards to companies in Ohio and their corresponding technologies are also discussed.

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.

77 FR 26674 - Enhancement of Electricity Market Surveillance and Analysis Through Ongoing Electronic Delivery...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-05-07

...; Order No. 760] Enhancement of Electricity Market Surveillance and Analysis Through Ongoing Electronic... ensure just and reasonable rates. \\1\\ 16 U.S.C. 825(b), 825f(a). II. Background 2. Wholesale electricity... consumers.\\4\\ \\2\\ A more in-depth discussion of developments in wholesale electricity markets--which no...

Ximelagatran (AstraZeneca).

PubMed

Hopfner, Rob

2002-02-01

AstraZeneca (formerly Astra) is developing ximelagatran, an orally active thrombin inhibitor and prodrug of melagatran, for the potential prevention and treatment of venous thromboembolism (VTE) in hip and knee replacement, for prevention of stroke in atrialfibrillation (AF) and for post acute coronary syndrome. As of December 1999, the compound was undergoing phase III trials for the prevention of VTE [349551]; these were ongoing in December 2001. By December 2000, ximelagatran had entered phase III trials for the prevention of stroke in atrial fibrillation [395212]. In September 2000, the company expected global NDA filing for this indication to take place in the middle of 2001 [383469]; however, in December 2000 this was revised to the second half of 2002 [395212], and in March 2001, to the second quarter of 2003 [402040], [416882], [431673]. By December 2000, a phase II trial was underway of ximelagatran as a potential treatment following myocardial infarction [395237]. In December 2001, early phase clinical trials were ongoing for post acute coronary syndrome [431673]. By December 2001, EU and US filings for VTE prevention were anticipated in the third quarter of 2002 and the second quarter of 2003, respectively [3144721, [350050], [431673]. Exanta is the trade name for both melagatran and ximelagatran. In 1998, marketing of ximelagatran in the US was to be assigned to the Astra/Merek joint marketing venture, prior to the merger [276577]. In April 1999, ABN predicted sales of 4 pounds million in 2003 [328676], [394606]. In December 2000, Lehman Brothers estimated peak sales to be $1.4 billion [394606]. At the same time, ABN-AMRO predicted peak sales of more than $1 billion [395237]. In June 2000, Deutsche Bank predicted sales of $70 million in 2002, rising to $245 million in 2003 [374500]. In September 2000, Merrill Lynch predicted sales of 125 pounds million in 2002, rising to 625 pounds million in 2004 [383742]. In February 2001, Merrill Lynch estimated that peak sales would reach $924 million in 2005 [429697].

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

PubMed

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

2008-03-20

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

Auditory closed-loop stimulation of the sleep slow oscillation enhances memory.

PubMed

Ngo, Hong-Viet V; Martinetz, Thomas; Born, Jan; Mölle, Matthias

2013-05-08

Brain rhythms regulate information processing in different states to enable learning and memory formation. The <1 Hz sleep slow oscillation hallmarks slow-wave sleep and is critical to memory consolidation. Here we show in sleeping humans that auditory stimulation in phase with the ongoing rhythmic occurrence of slow oscillation up states profoundly enhances the slow oscillation rhythm, phase-coupled spindle activity, and, consequently, the consolidation of declarative memory. Stimulation out of phase with the ongoing slow oscillation rhythm remained ineffective. Closed-loop in-phase stimulation provides a straight-forward tool to enhance sleep rhythms and their functional efficacy. Copyright © 2013 Elsevier Inc. All rights reserved.

Obeticholic Acid

PubMed Central

Smith, Susan M.; Pegram, Angela H.

2017-01-01

Objective: To review the pharmacology, efficacy, and safety of obeticholic acid (OCA) and determine its clinical role relative to other agents in the treatment of patients with primary biliary cholangitis (PBC). Data Sources: A PubMed search (1946 to November 2016) was conducted using the terms INT-747, obeticholic acid, OCA, farnesoid X receptor agonists, FXR agonists, primary biliary cirrhosis, and primary biliary cholangitis. Study Selection and Data Extraction: Phase II and III studies evaluating the use of OCA in PBC patients were included in this review. Data Synthesis: OCA, a farnesoid X receptor (FXR) agonist, is indicated for adult patients with PBC in combination with ursodeoxycholic acid (UDCA) or as monotherapy if unable to tolerate UDCA. Two clinical trials were identified evaluating OCA for the treatment of PBC. Study end points utilized biochemical markers (alkaline phosphatase [ALP] and bilirubin). A phase II study (n = 165) to determine efficacy and safety of OCA at 3 different doses (10 mg, 25 mg, 50 mg) demonstrated statistically significant reductions in ALP (P < .0001 for all OCA groups versus placebo) after 12 weeks. A phase III trial (n = 217) assessed lower OCA doses (5 mg and 10 mg) with a longer study duration (12 months). Statistically significant differences (P < .001) between the 5 to 10 mg group (46%) and the 10 mg group (47%) compared to the placebo group (10%) were found. The primary adverse effect reported in both trials was pruritus. Conclusions: OCA is the first FXR agonist approved for the treatment of PBC. Ongoing research to evaluate clinical outcomes with OCA is currently underway.

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

PubMed

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

2010-07-01

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

An update on vaccines for tuberculosis - there is more to it than just waning of BCG efficacy with time.

PubMed

Romano, Marta; Huygen, Kris

2012-12-01

Apart from better diagnostics and new anti-microbial drugs, an effective vaccine for tuberculosis is urgently needed to halt this poverty-related disease, afflicting millions of people worldwide. After a general introduction on the global threat of tuberculosis, the pros and cons of the existing M. bovis BCG vaccine are discussed. As the correlates of protection against tuberculosis remain largely unknown, new findings in biomarker research are described. Next, an update on the ongoing Phase I and Phase II clinical trials is given. Finally, some of the most promising novel pre-clinical developments using live attenuated vaccines, sub-unit vaccines, prime-boost strategies, and new vaccination routes are discussed. The field has made considerable progress and 12 vaccine candidates have now actually entered Phase I or Phase IIa and IIb clinical trials. It is argued that the variable protection conferred by the existing BCG vaccine against reactivation of latent TB is caused not only by waning of its efficacy with time but also by its weak induction of MHC class I restricted responses. Prime-boost strategies based on the actual BCG vaccine may not be sufficient to overcome this hurdle. The use of plasmid DNA vaccination might offer a solution.

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

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

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

1994-02-01

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

Technology evaluation: VEGF165 gene therapy, Valentis Inc.

PubMed

Morse, M A

2001-02-01

Valentis Inc, formerly GeneMedicine, is developing a vascular endothelial growth factor (VEGF165) non-viral gene therapy using its proprietary PINC polymer for plasmid condensation. Two physician-initiated phase II angioplasty trials are ongoing, one for treating peripheral vascular disease and one for treating coronary artery disease [281714], [347153]. In February 2000, the trials were expected to be completed in the fourth quarter of 2000 [356225]; however, in October 2000, it was reported that the trial for peripheral vascular disease would be completed in the first quarter of 2001 [385232]. In March 2000, Valentis initiated a trial incorporating Valentis's DOTMA-based cationic lipid gene delivery system and the VEGF165 gene with Eurogene's local collar-reservoir delivery device. The trial is designed to demonstrate that the VEGF165 gene, delivered locally to the outside surface of a blood vessel, will transfect and express in the smooth muscle cells of the vessel wall [360683]. In March 1999, Valentis was awarded with a Phase II SBIR grant of $686,260. The aim of grant was to advance the development of non-viral gene therapies for ischemia. Specifically, Valentis intended to select an optimal promoter to be used with the VEGF expression plasmid. Valentis also intended to evaluate the gene therapy system in a rabbit ischemia model and complete the necessary preclinical studies for submission of an IND [318137].

Refocusing research priorities in schools of nursing.

PubMed

Kulage, Kristine M; Ardizzone, Laura; Enlow, William; Hickey, Kathleen; Jeon, Christie; Kearney, Joan; Schnall, Rebecca; Larson, Elaine L

2013-01-01

It is critical for schools of nursing to periodically reassess their scholarly programs to ensure that their conceptual framework and approaches address current challenges and enhance productivity. This article describes the process undertaken at Columbia University School of Nursing to evaluate scholarly enterprise so that it remains relevant and responsive to changing trends and to revise our research conceptual model to be reflective of the foci of our clinicians and researchers. As part of a larger strategic initiative, a two-phase Research Excellence Planning and Implementation Workgroup was convened, consisting of a broad representation of faculty and administrative staff, with an overall goal of expanding scholarly capacity. During Phase I, members developed measurable outcomes and tactics and revised the school's conceptual research model. In Phase II, the workgroup implemented and monitored tactics and presented final recommendations to the dean. To measure progress, faculty members completed a survey to establish baseline scholarship and collaboration with results indicating room for growth in interdisciplinary and inter-institutional collaboration. Ongoing assessment of outcomes includes Web-based tracking of scholarly activities and follow-up surveys to monitor expansion of faculty collaboration. We recommend this process to other schools committed to sustainable, increasingly relevant scholarship. Copyright © 2013 Elsevier Inc. All rights reserved.

Old and new acetylcholinesterase inhibitors for Alzheimer's disease.

PubMed

Galimberti, Daniela; Scarpini, Elio

2016-10-01

To date, pharmacological treatment of Alzheimer's disease (AD) includes Acetylcholinesterase Inhibitors (AChEIs) for mild-to-moderate AD, and memantine for moderate-to-severe AD. AChEIs reversibly inhibit acetylcholinesterase (AChE), thus increasing the availability of acetylcholine in cholinergic synapses, enhancing cholinergic transmission. These drugs provide symptomatic short-term benefits, without clearly counteracting the progression of the disease. On the wake of successful clinical trials which lead to the marketing of AChEIs donepezil, rivastigmine and galantamine, many compounds with AChEI properties have been developed and tested mainly in Phase I-II clinical trials in the last twenty years. Here, we review clinical trials initiated and interrupted, and those ongoing so far. Despite many clinical trials with novel AChEIs have been carried out after the registration of those currently used to treat mild to moderate AD, none so far has been successful in a Phase III trial and marketed. Alzheimer's disease is a complex multifactorial disorder, therefore therapy should likely address not only the cholinergic system but also additional neurotransmitters. Moreover, such treatments should be started in very mild phases of the disease, and preventive strategies addressed in elderly people.

Waste inspection tomography (WIT)

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

Bernardi, R.T.

1996-12-31

WIT is a self-sufficient mobile semitrailer for nondestructive evaluation and nondestructive assay of nuclear waste drums using x-ray and gamma-ray tomography. The recently completed Phase I included the design, fabrication, and initial testing of all WIT subsystems installed on-board the trailer. Initial test results include 2 MeV digital radiography, computed tomography, Anger camera imaging, single photon emission computed tomography, gamma-ray spectroscopy, collimated gamma scanning, and active and passive computed tomography using a 1.4 mCi source of {sup 166}Ho. These techniques were initially demonstrated on a 55-gallon phantom drum with 3 simulated waste matrices of combustibles, heterogeneous metals, and cement usingmore » check sources of gamma active isotopes such as {sup 137}Cs and {sup 133}Ba with 9-250 {mu}Ci activities. Waste matrix identification, isotopic identification, and attenuation-corrected gamma activity determination were demonstrated nondestructively and noninvasively in Phase I. Currently ongoing Phase II involves DOE site field test demonstrations at LLNL, RFETS, and INEL with real nuclear waste drums. Current WIT experience includes 55 gallon drums of cement, graphite, sludge, glass, metals, and combustibles. Thus far WIT has inspected drums with 0-20 gms of {sup 239}Pu.« less

Porous titanium and Ti-35Nb alloy: effects on gene expression of osteoblastic cells derived from human alveolar bone.

PubMed

do Prado, Renata Falchete; Rabêlo, Sylvia Bicalho; de Andrade, Dennia Perez; Nascimento, Rodrigo Dias; Henriques, Vinicius André Rodrigues; Carvalho, Yasmin Rodarte; Cairo, Carlos Alberto Alves; de Vasconcellos, Luana Marotta Reis

2015-11-01

Tests on titanium alloys that possess low elastic modulus, corrosion resistance and minimal potential toxicity are ongoing. This study aimed to evaluate the behavior of human osteoblastic cells cultured on dense and porous Titanium (Ti) samples comparing to dense and porous Ti-35 Niobium (Ti-35Nb) samples, using gene expression analysis. Scanning electronic microscopy confirmed surface porosity and pore interconnectivity and X-ray diffraction showed titanium beta-phase stabilization in Ti-35Nb alloy. There were no differences in expression of transforming growth factor-β, integrin-β1, alkaline phosphatase, osteopontin, macrophage colony stimulating factor, prostaglandin E synthase, and apolipoprotein E regarding the type of alloy, porosity and experimental period. The experimental period was a significant factor for the markers: bone sialoprotein II and interleukin 6, with expression increasing over time. Porosity diminished Runt-related transcription factor-2 (Runx-2) expression. Cells adhering to the Ti-35Nb alloy showed statistically similar expression to those adhering to commercially pure Ti grade II, for all the markers tested. In conclusion, the molecular mechanisms of interaction between human osteoblasts and the Ti-35Nb alloy follow the principal routes of osseointegration of commercially pure Ti grade II. Porosity impaired the route of transcription factor Runx-2.

A Serological Biopsy Using Five Stomach-Specific Circulating Biomarkers for Gastric Cancer Risk Assessment: A Multi-Phase Study.

PubMed

Tu, Huakang; Sun, Liping; Dong, Xiao; Gong, Yuehua; Xu, Qian; Jing, Jingjing; Bostick, Roberd M; Wu, Xifeng; Yuan, Yuan

2017-05-01

We aimed to assess a serological biopsy using five stomach-specific circulating biomarkers-pepsinogen I (PGI), PGII, PGI/II ratio, anti-Helicobacter pylori (H. pylori) antibody, and gastrin-17 (G-17)-for identifying high-risk individuals and predicting risk of developing gastric cancer (GC). Among 12,112 participants with prospective follow-up from an ongoing population-based screening program using both serology and gastroscopy in China, we conducted a multi-phase study involving a cross-sectional analysis, a follow-up analysis, and an integrative risk prediction modeling analysis. In the cross-sectional analysis, the five biomarkers (especially PGII, the PGI/II ratio, and H. pylori sero-positivity) were associated with the presence of precancerous gastric lesions or GC at enrollment. In the follow-up analysis, low PGI levels and PGI/II ratios were associated with higher risk of developing GC, and both low (<0.5 pmol/l) and high (>4.7 pmol/l) G-17 levels were associated with higher risk of developing GC, suggesting a J-shaped association. In the risk prediction modeling analysis, the five biomarkers combined yielded a C statistic of 0.803 (95% confidence interval (CI)=0.789-0.816) and improved prediction beyond traditional risk factors (C statistic from 0.580 to 0.811, P<0.001) for identifying precancerous lesions at enrollment, and higher serological biopsy scores based on the five biomarkers at enrollment were associated with higher risk of developing GC during follow-up (P for trend <0.001). A serological biopsy composed of the five stomach-specific circulating biomarkers could be used to identify high-risk individuals for further diagnostic gastroscopy, and to stratify individuals' risk of developing GC and thus to guide targeted screening and precision prevention.

Report on Partial Findings of an Ongoing Research: Social Networking Sites (SNS) as a Platform to Support Teaching and Learning in Secondary Schools

ERIC Educational Resources Information Center

Bt. Ubaidullah, Nor Hasbiah; Samsuddin, Khairulanuar; Bt. Fabil, Norsikin; Bt. Mahadi, Norhayati

2011-01-01

This paper reports the partial findings of a survey that was carried out in the analysis phase of an ongoing research for the development of a prototype of a Social Networking Site (SNS) to support teaching and learning in secondary schools. For the initial phase of the study, a quantitative research method was used based on a survey involving 383…

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

PubMed

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

2017-06-01

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

SMARTE: NEXT STEPS

EPA Science Inventory

SMARTe will be developed in an overlapping phased approach. The first phase began in 2003 and focused on the collection of information and resources and the transfer of this data. This phase is ongoing as information and resources are updated annually. The second phase began in 2...

Randomized comparison of next-generation sequencing and array comparative genomic hybridization for preimplantation genetic screening: a pilot study.

PubMed

Yang, Zhihong; Lin, James; Zhang, John; Fong, Wai Ieng; Li, Pei; Zhao, Rong; Liu, Xiaohong; Podevin, William; Kuang, Yanping; Liu, Jiaen

2015-06-23

Recent advances in next-generation sequencing (NGS) have provided new methods for preimplantation genetic screening (PGS) of human embryos from in vitro fertilization (IVF) cycles. However, there is still limited information about clinical applications of NGS in IVF and PGS (IVF-PGS) treatments. The present study aimed to investigate the effects of NGS screening on clinical pregnancy and implantation outcomes for PGS patients in comparison to array comparative genomic hybridization (aCGH) screening. This study was performed in two phases. Phase I study evaluated the accuracy of NGS for aneuploidy screening in comparison to aCGH. Whole-genome amplification (WGA) products (n = 164) derived from previous IVF-PGS cycles (n = 38) were retrospectively analyzed with NGS. The NGS results were then compared with those of aCGH. Phase II study further compared clinical pregnancy and implantation outcomes between NGS and aCGH for IVF-PGS patients. A total of 172 patients at mean age 35.2 ± 3.5 years were randomized into two groups: 1) NGS (Group A): patients (n = 86) had embryos screened with NGS and 2) aCGH (Group B): patients (n = 86) had embryos screened with aCGH. For both groups, blastocysts were vitrified after trophectoderm biopsy. One to two euploid blastocysts were thawed and transferred to individual patients primarily based on the PGS results. Ongoing pregnancy and implantation rates were compared between the two study groups. NGS detected all types of aneuploidies of human blastocysts accurately and provided a 100 % 24-chromosome diagnosis consistency with the highly validated aCGH method. Moreover, NGS screening identified euploid blastocysts for transfer and resulted in similarly high ongoing pregnancy rates for PGS patients compared to aCGH screening (74.7 % vs. 69.2 %, respectively, p >0.05). The observed implantation rates were also comparable between the NGS and aCGH groups (70.5 % vs. 66.2 %, respectively, p >0.05). While NGS screening has been recently introduced to assist IVF patients, this is the first randomized clinical study on the efficiency of NGS for preimplantation genetic screening in comparison to aCGH. With the observed high accuracy of 24-chromosome diagnosis and the resulting high ongoing pregnancy and implantation rates, NGS has demonstrated an efficient, robust high-throughput technology for PGS.

47 CFR 54.309 - Connect America Fund Phase II Public Interest Obligations.

Code of Federal Regulations, 2014 CFR

2014-10-01

... 47 Telecommunication 3 2014-10-01 2014-10-01 false Connect America Fund Phase II Public Interest Obligations. 54.309 Section 54.309 Telecommunication FEDERAL COMMUNICATIONS COMMISSION (CONTINUED) COMMON... Connect America Fund Phase II Public Interest Obligations. (a) A price cap carrier electing Phase II model...

Emerging therapies for Parkinson's disease.

PubMed

Poewe, Werner; Mahlknecht, Philipp; Jankovic, Joseph

2012-08-01

The experimental therapeutics of Parkinson's disease are reviewed, highlighting the current pipeline of emerging therapeutic approaches. This review includes novel approaches to dopaminergic drug delivery such as intraintestinal infusions or new extended-release formulations of levodopa and also intrapulmonary delivery of apomorphine as well as novel dopaminergic agents like the monoamine oxidase-B inhibitor safinamide or novel catechol-O-methyl transferase inhibitors. An even greater number of ongoing clinical trials assess the efficacy and safety of nondopaminergic approaches to enhance motor control or reduce motor complications like fluctuations and dyskinesias. These include adenosine A2A antagonists, α-adrenergic and serotonergic agonists as well as drugs acting on the glutamatergic system. Gene-based or cell-based intrastriatal delivery of therapeutic principles that enhance striatal dopaminergic transmission directly or via the stimulation of trophic activity has also reached phase II clinical development with encouraging results in some studies. Finally, a wide spectrum of agents with a potential for slowing disease progression is currently tested. A variety of medical and nonmedical interventions in different phases of clinical development provide an interesting and promising portfolio of emerging therapies for Parkinson's disease.

The aliens inside us: HERV-W endogenous retroviruses and multiple sclerosis.

PubMed

Dolei, Antonina

2018-01-01

Two human endogenous retroviruses of the HERV-W family are proposed as multiple sclerosis (MS) co-factors: MS-associated retrovirus (MSRV) and ERVWE1, whose env proteins showed several potentially neuropathogenic features, in vitro and in animal models. Phase II clinical trials against HERV-Wenv are ongoing. HERV-W/MSRV was repeatedly found in MS patients, in striking parallel with MS stages, active/remission phases, and therapy outcome. The HERV-Wenv protein is highly expressed in active MS plaques. Early MSRV presence in spinal fluids predicted worst MS progression 10 years in advance. Effective anti-MS therapies strongly reduced MSRV/Syncytin-1/HERV-W expression. The Epstein-Barr virus (EBV) activates HERV-W/MSRV in vitro and in vivo, in patients with infectious mononucleosis and controls with high anti-EBNA1-IgG titers. Thus, the two main EBV/MS links (infectious mononucleosis and high anti-EBNA1-IgG titers) are paralleled by activation of HERV-W/MSRV. It is hypothesized that EBV may act as initial trigger of future MS, years later, by activating MSRV, which would act as direct neuropathogenic effector, before and during MS.

Advances in immunotherapy for the treatment of glioblastoma.

PubMed

Tivnan, Amanda; Heilinger, Tatjana; Lavelle, Ed C; Prehn, Jochen H M

2017-01-01

Glioblastoma (GBM) is an aggressive brain tumour, associated with extremely poor prognosis and although there have been therapeutic advances, treatment options remain limited. This review focuses on the use of immunotherapy, harnessing the power of the host's immune system to reject cancer cells. Key challenges in glioma specific immunotherapy as with many other cancers are the limited immunogenicity of the cancer cells and the immunosuppressive environment of the tumour. Although specific antigens have been identified in several cancers; brain tumours, such as GBM, are considered poorly immunogenic. However, as detailed in this review, strategies aimed at circumventing these challenges are showing promise for GBM treatment; including identification of glioma specific antigens and endogenous immune cell activation in an attempt to overcome the immunosuppressive environment which is associated with GBM tumours. An up-to-date summary of current Phase I/II and ongoing Phase III GBM immunotherapy clinical trials is provided in addition to insights into promising preclinical approaches which are focused predominantly on increased induction of Type 1 helper T cell (T h 1) immune responses within patients.

Tagatose: from a sweetener to a new diabetic medication?

PubMed

Espinosa, Ikna; Fogelfeld, Leon

2010-02-01

Tagatose is a naturally occurring simple sugar that is a more palatable bulk low-calorie (1.5 kcal/g) sweetener. It was approved as a food additive by the FDA in 2003. Tagatose has been studied as a potential antidiabetic and antiobesity medication. In preliminary studies in humans, tagatose has shown a low postprandial blood glucose and insulin response. Its proposed mechanism of action may involve interference in the absorption of carbohydrates by inhibiting intestinal disaccharidases and glucose transport. It may also act through hepatic inhibition of glycogenolysis. This article summarizes tagatose Phase I and II diabetes trials. It describes the pharmacodynamics and possible mechanism of action of this agent. Literature from 1974 to 2009 is reviewed. Better understanding of the implications of postprandial hyperglycemia. An appreciation of the liver as a target of glucose control. Increased awareness of tagatose, a sweetener, as a potential new medication that operates through improvement of postprandial hyperglycemia. Tagatose is currently being studied as a postprandial antihyperglycemic agent that may be safer with regard to hypoglycemia. Ongoing Phase III clinical trials will provide more definitive answers.

Andexanet alfa to reverse the anticoagulant activity of factor Xa inhibitors: a review of design, development and potential place in therapy.

PubMed

Sartori, Michelangelo; Cosmi, Benilde

2018-04-01

Direct oral anticoagulants are associated with rates of major bleeding which are not negligible, albeit lower than those associated with vitamin K antagonists. No specific reversal agent for factor Xa (FXa) direct inhibitors is currently available for clinical use. A modified activated human FXa decoy protein, andexanet alfa, is being developed that binds FXa direct inhibitors in their active site, thus reversing their anticoagulant effect. The purpose of this article is to review the design, development and clinical trials of andexanet alfa. Andexanet alfa was shown to reverse FXa inhibitors anticoagulant activity both in thrombosis animal models, healthy volunteers and patients with acute major bleeding. Andexanet alfa has been studied in double-blind, placebo-controlled phase II and III studies. A preliminary report of the phase III study showed that an effective hemostasis was obtained after andexanet alfa infusion in the majority of the patients with acute major bleeding associated with FXa inhibitors. Additional studies are ongoing and andexanet alfa is expected to be launched in the market in the near future.

Central implementation strategies outperform local ones in improving HIV testing in Veterans Healthcare Administration facilities.

PubMed

Goetz, Matthew Bidwell; Hoang, Tuyen; Knapp, Herschel; Burgess, Jane; Fletcher, Michael D; Gifford, Allen L; Asch, Steven M

2013-10-01

Pilot data suggest that a multifaceted approach may increase HIV testing rates, but the scalability of this approach and the level of support needed for successful implementation remain unknown. To evaluate the effectiveness of a scaled-up multi-component intervention in increasing the rate of risk-based and routine HIV diagnostic testing in primary care clinics and the impact of differing levels of program support. Three arm, quasi-experimental implementation research study. Veterans Health Administration (VHA) facilities. Persons receiving primary care between June 2009 and September 2011 INTERVENTION: A multimodal program, including a real-time electronic clinical reminder to facilitate HIV testing, provider feedback reports and provider education, was implemented in Central and Local Arm Sites; sites in the Central Arm also received ongoing programmatic support. Control Arm sites had no intervention Frequency of performing HIV testing during the 6 months before and after implementation of a risk-based clinical reminder (phase I) or routine clinical reminder (phase II). The adjusted rate of risk-based testing increased by 0.4 %, 5.6 % and 10.1 % in the Control, Local and Central Arms, respectively (all comparisons, p < 0.01). During phase II, the adjusted rate of routine testing increased by 1.1 %, 6.3 % and 9.2 % in the Control, Local and Central Arms, respectively (all comparisons, p < 0.01). At study end, 70-80 % of patients had been offered an HIV test. Use of clinical reminders, provider feedback, education and social marketing significantly increased the frequency at which HIV testing is offered and performed in VHA facilities. These findings support a multimodal approach toward achieving the goal of having every American know their HIV status as a matter of routine clinical practice.

Efficacy and safety of Lian-Ju-Gan-Mao capsules for treating the common cold with wind-heat syndrome: study protocol for a randomized controlled trial.

PubMed

Wang, Shengjun; Jiang, Hongli; Yu, Qin; She, Bin; Mao, Bing

2017-01-05

The common cold is a common and frequent respiratory disease mainly caused by viral infection of the upper respiratory tract. Chinese herbal medicine has been increasingly prescribed to treat the common cold; however, there is a lack of evidence to support the wide utility of this regimen. This protocol describes an ongoing phase II randomized controlled clinical trial, based on the theory of traditional Chinese medicine (TCM), with the objective of evaluating the efficacy and safety of Lian-Ju-Gan-Mao capsules (LJGMC), a Chinese patent medicine, compared with placebo in patients suffering from the common cold with wind-heat syndrome (CCWHS). This is a multicenter, randomized, double-blind, placebo-controlled phase II clinical trial. A total of 240 patients will be recruited and randomly assigned to a high-dose group, medium-dose group, low-dose group, and placebo-matched group in a 1:1:1:1 ratio. The treatment course is 3 consecutive days, with a 5-day follow-up. The primary outcome is time to all symptoms' clearance. Secondary outcomes include time to the disappearance of primary symptoms and each secondary symptom, time to fever relief, time to fever clearance, and change in TCM symptom and sign scores. This trial is a well-designed study according to principles and regulations issued by the China Food and Drug Administration (CFDA). The results will provide high-quality evidence on the efficacy and safety of LJGMC in treating CCWHS and help to optimize the dose for the next phase III clinical trial. Moreover, the protocol presents a detailed and practical methodology for future clinical trials of drugs developed based on TCM. Chinese Clinical Trial Registry, ChiCTR-IPR-15006504 . Registered on 4 June 2015.

Evolution of an International External Quality Assurance Model To Support Laboratory Investigation of Streptococcus pneumoniae, Developed for the SIREVA Project in Latin America, from 1993 to 2005▿

PubMed Central

Lovgren, Marguerite; Talbot, James A.; Brandileone, Maria Cristina; Casagrande, Silvana T.; Agudelo, Clara Inés; Castañeda, Elizabeth; Regueira, Mabel; Corso, Alejandra; Heitmann, Ingrid; Maldonado, Aurora; Echániz-Avilés, Gabriela; Soto-Noguerón, Araceli; Hortal, María; Camou, Teresa; Gabastou, Jean-Marc; Fabio, José Luis Di

2007-01-01

In 1993 the Pan American Health Organization initiated a laboratory-based surveillance system, called the SIREVA project, to learn about Streptococcus pneumoniae invasive disease in Latin American children. In 1994, National Laboratories in six countries were trained to perform serotyping and antibiotic susceptibility testing using broth microdilution to determine the MIC for specified antibiotics. An international External Quality Assurance (EQA) program was developed to monitor and support ongoing laboratory performance. The EQA program was coordinated by the National Centre for Streptococcus (NCS), Edmonton, Canada, and included external proficiency testing (EPT) and a validation process requiring regular submission of a sample of isolates from each laboratory to the NCS for verification of the serotype and MIC. In 1999, the EQA program was decentralized to use three of the original laboratories as regional quality control centers to address operational concerns and to accommodate the growth of the laboratory network to more than 20 countries including the Caribbean region. The overall EPT serotyping accuracies for phase I (1993 to 1998) and phase II (1999 to 2005) were 88.0 and 93.8%, respectively; the MIC correlations within ±1 log2 dilution of the expected result were 83.0 and 91.0% and the interpretive category agreements were 89.1 and 95.3%. Overall, the validation process serotyping accuracies for phases I and II were 81.9 and 88.1%, respectively, 80.4 and 90.5% for MIC agreement, and 85.8 and 94.3% for category agreement. These results indicate a high level of testing accuracy in participating National Laboratories and a sustained increase in EQA participation in Latin America and the Caribbean. PMID:17687007

Herpes Zoster Infection in Patients With Ulcerative Colitis Receiving Tofacitinib.

PubMed

Winthrop, Kevin L; Melmed, Gil Y; Vermeire, Séverine; Long, Millie D; Chan, Gary; Pedersen, Ronald D; Lawendy, Nervin; Thorpe, Andrew J; Nduaka, Chudy I; Su, Chinyu

2018-05-30

Tofacitinib is an oral, small molecule Janus kinase inhibitor that is being investigated for ulcerative colitis (UC). Tofacitinib is approved for rheumatoid arthritis and psoriatic arthritis, where it has been shown to increase herpes zoster (HZ) risk. We evaluated HZ risk among UC patients using tofacitinib. HZ cases were identified in tofacitinib phase II/III/ongoing, open-label, long-term extension (OLE) UC trials. We calculated HZ incidence rates (IRs) per 100 patient-years of tofacitinib exposure within phase III maintenance (Maintenance Cohort) and phase II/III/OLE (Overall Cohort) studies, stratified by baseline demographics and other factors. HZ risk factors were evaluated in the Overall Cohort using Cox proportional hazard models. Overall, 65 (5.6%) patients developed HZ. Eleven patients had multidermatomal involvement (2 nonadjacent or 3-6 adjacent dermatomes), and 1 developed encephalitis (resolved upon standard treatment). Five (7.7%) events led to treatment discontinuation. HZ IR (95% confidence interval [CI]) in the Overall Cohort was 4.07 (3.14-5.19) over a mean (range) of 509.1 (1-1606) days, with no increased risk observed with increasing tofacitinib exposure. IRs (95% CI) were highest in patients age ≥65 years, 9.55 (4.77-17.08); Asian patients, 6.49 (3.55-10.89); patients with prior tumor necrosis factor inhibitor (TNFi) failure, 5.38 (3.86-7.29); and patients using tofacitinib 10 mg twice daily, 4.25 (3.18-5.56). Multivariate analysis identified older age and prior TNFi failure as independent risk factors. In tofacitinib-treated UC patients, there was an elevated risk of HZ, although complicated HZ was infrequent. Increased HZ rates occurred in patients who were older, Asian, or had prior TNFi failure (NCT00787202, NCT01465763, NCT01458951, NCT01458574, NCT01470612).

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

PubMed Central

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

2010-01-01

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

Omitting elective nodal irradiation during thoracic irradiation in limited-stage small cell lung cancer--evidence from a phase II trial.

PubMed

Colaco, Rovel; Sheikh, Hamid; Lorigan, Paul; Blackhall, Fiona; Hulse, Paul; Califano, Raffaele; Ashcroft, Linda; Taylor, Paul; Thatcher, Nicholas; Faivre-Finn, Corinne

2012-04-01

Omitting elective nodal irradiation (ENI) in limited-stage disease small cell lung cancer (LD-SCLC) is expected to result in smaller radiation fields. We report on data from a randomised phase II trial that omitted ENI in patients receiving concurrent chemo-radiotherapy for LD-SCLC. 38 patients with LD-SCLC were randomised to receive once-daily (66 Gy in 33 fractions) or twice-daily (45 Gy in 30 fractions) radiotherapy (RT). 3D-conformal RT was given concurrently with cisplatin and etoposide starting with the second cycle of a total of four cycles. The gross tumour volume was defined as primary tumour with involved lymph nodes (nodes ≥1 cm in short axis) identifiable with CT imaging. ENI was not used. Six recurrence patterns were identified: recurrence within planning target volume (PTV) only, recurrence within PTV+regional nodal recurrence and/or distant recurrence, isolated nodal recurrence outside PTV, nodal recurrence outside PTV+distant recurrence, distant metastases only and no recurrence. At median follow-up 16.9 months, 31/38 patients were evaluable and 14/31 patients had relapsed. There were no isolated nodal recurrences. Eight patients relapsed with intra-thoracic disease: 2 within PTV only, 4 within PTV and distantly and 2 with nodal recurrence outside PTV plus distant metastases. Rates of grade 3+ acute oesophagitis and pneumonitis in the 31 evaluable patients were 23 and 3% respectively. In our study of LD-SCLC, omitting ENI based on CT imaging was not associated with a high risk of isolated nodal recurrence, although further prospective studies are needed to confirm this. Routine ENI omission will be further evaluated prospectively in the ongoing phase III CONVERT trial (NCT00433563). Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Preoperative chemoradiation with paclitaxel-carboplatin or with fluorouracil-oxaliplatin-folinic acid (FOLFOX) for resectable esophageal and junctional cancer: the PROTECT-1402, randomized phase 2 trial.

PubMed

Messager, Mathieu; Mirabel, Xavier; Tresch, Emmanuelle; Paumier, Amaury; Vendrely, Véronique; Dahan, Laetitia; Glehen, Olivier; Vasseur, Frederique; Lacornerie, Thomas; Piessen, Guillaume; El Hajbi, Farid; Robb, William B; Clisant, Stéphanie; Kramar, Andrew; Mariette, Christophe; Adenis, Antoine

2016-05-18

Often curative treatment for locally advanced resectable esophageal or gastro-esophageal junctional cancer consists of concurrent neoadjuvant radiotherapy and chemotherapy followed by surgery. Currently, one of the most commonly used chemotherapy regimens in this setting is a combination of a fluoropyrimidin and of a platinum analogue. Due to the promising results of the recent CROSS trial, another regimen combining paclitaxel and carboplatin is also widely used by European and American centers. No clinical study has shown the superiority of one treatment over the other. The objective of this Phase II study is to clarify clinical practice by comparing these two chemotherapy treatments. Our aim is to evaluate, in operable esophageal and gastro-esophageal junctional cancer, the complete resection rate and severe postoperative morbidity rate associated with these two neoadjuvant chemotherapeutic regimens (carboplatin-paclitaxel or fluorouracil-oxaliplatin-folinic acid) when each is combined with the radiation regime utilized in the CROSS trial. PROTECT is a prospective, randomized, multicenter, open arms, phase II trial. Eligible patients will have a histologically confirmed adenocarcinoma or squamous cell carcinoma and be treated with neoadjuvant radiochemotherapy followed by surgery for stage IIB or stage III resectable esophageal cancer. A total of 106 patients will be randomized to receive either 3 cycles of FOLFOX combined to concurrent radiotherapy (41.4 Grays) or carboplatin and paclitaxel with the same radiation regimen, using a 1:1 allocation ratio. This ongoing trial offers the unique opportunity to compare two standards of chemotherapy delivered with a common regimen of preoperative radiation, in the setting of operable locally advanced esophageal or gastro-esophageal junctional tumors. NCT02359968 (ClinicalTrials.gov) (registration date: 9 FEB 2015), EudraCT: 2014-000649-62 (registration date: 10 FEB 2014).

THE HCN/HNC ABUNDANCE RATIO TOWARD DIFFERENT EVOLUTIONARY PHASES OF MASSIVE STAR FORMATION

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

Jin, Mihwa; Lee, Jeong-Eun; Kim, Kee-Tae, E-mail: mihwajin.sf@gmail.com, E-mail: jeongeun.lee@khu.ac.kr, E-mail: ktkim@kasi.re.kr

2015-07-20

Using the H{sup 13}CN and HN{sup 13}C J = 1–0 line observations, the abundance ratio of HCN/HNC has been estimated for different evolutionary stages of massive star formation: infrared dark clouds (IRDCs), high-mass protostellar objects (HMPOs), and ultracompact H ii regions (UCH iis). IRDCs were divided into “quiescent IRDC cores (qIRDCc)” and “active IRDC cores (aIRDCc),” depending on star formation activity. The HCN/HNC ratio is known to be higher at active and high temperature regions related to ongoing star formation, compared to cold and quiescent regions. Our observations toward 8 qIRDCc, 16 aIRDCc, 23 HMPOs, and 31 UCH iis showmore » consistent results; the ratio is 0.97 (±0.10), 2.65 (±0.88), 4.17 (±1.03), and 8.96 (±3.32) in these respective evolutionary stages, increasing from qIRDCc to UCH iis. The change of the HCN/HNC abundance ratio, therefore, seems directly associated with the evolutionary stages of star formation, which have different temperatures. One suggested explanation for this trend is the conversion of HNC to HCN, which occurs effectively at higher temperatures. To test the explanation, we performed a simple chemical model calculation. In order to fit the observed results, the energy barrier of the conversion must be much lower than the value provided by theoretical calculations.« less

Isac Sc-Linac Phase-II Helium Refrigerator Commissioning and First Operational Experience at Triumf

NASA Astrophysics Data System (ADS)

Sekachev, I.; Kishi, D.; Laxdal, R. E.

2010-04-01

ISAC Phase-II is an upgrade of the radioactive isotope superconducting linear accelerator, SC-linac, at TRIUMF. The Phase-I section of the accelerator, medium-beta, is operational and is cooled with a 600 W helium refrigerator, commissioned in March 2005. An identical refrigerator is being used with the Phase-II segment of the accelerator; which is now under construction. The second refrigerator has been commissioned and tested with the Phase-I section of the linac and is used for Phase-II linac development, including new SC-cavity performance tests. The commissioning of the Phase-II refrigeration system and recent operational experience is presented.

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.

78 FR 76789 - Additional Connect America Fund Phase II Issues

Federal Register 2010, 2011, 2012, 2013, 2014

2013-12-19

... inspection and copying during normal business hours in the FCC Reference Information Center, Portals II, 445... Phase I to Phase II. 2. Timing of Phase II Support Disbursements. In the USF/ICC Transformation Order... language in paragraph 180 of the USF/ICC Transformation Order. We now seek to more fully develop the record...

48 CFR 1852.219-81 - Limitation on subcontracting-SBIR Phase II program.

Code of Federal Regulations, 2014 CFR

2014-10-01

... subcontracting-SBIR Phase II program. 1852.219-81 Section 1852.219-81 Federal Acquisition Regulations System... CLAUSES Texts of Provisions and Clauses 1852.219-81 Limitation on subcontracting—SBIR Phase II program. As prescribed in 1819.7302(b), insert the following clause: Limitation on Subcontracting—SBIR Phase II Program...

48 CFR 1852.219-81 - Limitation on subcontracting-SBIR Phase II program.

Code of Federal Regulations, 2013 CFR

2013-10-01

... subcontracting-SBIR Phase II program. 1852.219-81 Section 1852.219-81 Federal Acquisition Regulations System... CLAUSES Texts of Provisions and Clauses 1852.219-81 Limitation on subcontracting—SBIR Phase II program. As prescribed in 1819.7302(b), insert the following clause: Limitation on Subcontracting—SBIR Phase II Program...

48 CFR 1852.219-81 - Limitation on subcontracting-SBIR Phase II program.

Code of Federal Regulations, 2012 CFR

2012-10-01

... subcontracting-SBIR Phase II program. 1852.219-81 Section 1852.219-81 Federal Acquisition Regulations System... CLAUSES Texts of Provisions and Clauses 1852.219-81 Limitation on subcontracting—SBIR Phase II program. As prescribed in 1819.7302(b), insert the following clause: Limitation on Subcontracting—SBIR Phase II Program...

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

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

PubMed Central

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

2015-01-01

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

FDA Approval: Palbociclib for the Treatment of Postmenopausal Patients with Estrogen Receptor-Positive, HER2-Negative Metastatic Breast Cancer.

PubMed

Beaver, Julia A; Amiri-Kordestani, Laleh; Charlab, Rosane; Chen, Wei; Palmby, Todd; Tilley, Amy; Zirkelbach, Jeanne Fourie; Yu, Jingyu; Liu, Qi; Zhao, Liang; Crich, Joyce; Chen, Xiao Hong; Hughes, Minerva; Bloomquist, Erik; Tang, Shenghui; Sridhara, Rajeshwari; Kluetz, Paul G; Kim, Geoffrey; Ibrahim, Amna; Pazdur, Richard; Cortazar, Patricia

2015-11-01

On February 3, 2015, the FDA granted accelerated approval to palbociclib (IBRANCE, Pfizer Inc.), an inhibitor of cyclin-dependent kinases 4 and 6 (CDK4 and CDK6), for use in combination with letrozole for the treatment of postmenopausal women with estrogen receptor (ER)-positive, HER2-negative advanced breast cancer as initial endocrine-based therapy for their metastatic disease. The approval is based on a randomized, multicenter, open-label phase I/II trial (PALOMA-1) in 165 patients randomized to palbociclib (125 mg orally daily for 21 consecutive days, followed by 7 days off treatment) plus letrozole (2.5 mg orally daily) or letrozole alone. The phase II portion of the trial was divided into two cohorts: cohort 1 enrolled 66 biomarker-unselected patients and cohort 2 enrolled 99 biomarker-positive patients. The major efficacy outcome measure was investigator-assessed progression-free survival (PFS). A large magnitude of improvement in PFS was observed in patients receiving palbociclib plus letrozole compared with patients receiving letrozole alone (HR, 0.488; 95% confidence interval, 0.319-0.748). Multiple sensitivity analyses were supportive of clinical benefit. The most common adverse reaction in patients receiving palbociclib plus letrozole was neutropenia. This article summarizes the FDA thought process and data supporting accelerated approval based on PALOMA-1 that may be contingent upon verification and description of clinical benefit in the ongoing and fully accrued confirmatory trial PALOMA-2. ©2015 American Association for Cancer Research.

Progress in the Development of Metamorphic Multi-Junction III-V Space-Solar Cells at Essential Research Incorporated

NASA Technical Reports Server (NTRS)

Sinharoy, Samar; Patton, Martin O.; Valko, Thomas M., Sr.; Weizer, Victor G.

2002-01-01

Theoretical calculations have shown that highest efficiency III-V multi-junction solar cells require alloy structures that cannot be grown on a lattice-matched substrate. Ever since the first demonstration of high efficiency metamorphic single junction 1.1 eV and 1.2 eV InGaAs solar cells by Essential Research Incorporated (ERI), interest has grown in the development of multi-junction cells of this type using graded buffer layer technology. ERI is currently developing a dual-junction 1.6 eV InGaP/1.1 eV InGaAs tandem cell (projected practical air-mass zero (AM0), one-sun efficiency of 28%, and 100-sun efficiency of 37.5%) under a Ballistic Missile Defense Command (BMDO) SBIR Phase II program. A second ongoing research effort at ERI involves the development of a 2.1 eV AlGaInP/1.6 eV InGaAsP/1.2 eV InGaAs triple-junction concentrator tandem cell (projected practical AM0 efficiency of 36.5% under 100 suns) under a SBIR Phase II program funded by the Air Force. We are in the process of optimizing the dual-junction cell performance. In case of the triple-junction cell, we have developed the bottom and the middle cell, and are in the process of developing the layer structures needed for the top cell. A progress report is presented in this paper.

Challenges Facing Early Phase Trials Sponsored by the National Cancer Institute: An Analysis of Corrective Action Plans to Improve Accrual.

PubMed

Massett, Holly A; Mishkin, Grace; Rubinstein, Larry; Ivy, S Percy; Denicoff, Andrea; Godwin, Elizabeth; DiPiazza, Kate; Bolognese, Jennifer; Zwiebel, James A; Abrams, Jeffrey S

2016-11-15

Accruing patients in a timely manner represents a significant challenge to early phase cancer clinical trials. The NCI Cancer Therapy Evaluation Program analyzed 19 months of corrective action plans (CAP) received for slow-accruing phase I and II trials to identify slow accrual reasons, evaluate whether proposed corrective actions matched these reasons, and assess the CAP impact on trial accrual, duration, and likelihood of meeting primary scientific objectives. Of the 135 CAPs analyzed, 69 were for phase I trials and 66 for phase II trials. Primary reasons cited for slow accrual were safety/toxicity (phase I: 48%), design/protocol concerns (phase I: 42%, phase II: 33%), and eligibility criteria (phase I: 41%, phase II: 35%). The most commonly proposed corrective actions were adding institutions (phase I: 43%, phase II: 85%) and amending the trial to change eligibility or design (phase I: 55%, phase II: 44%). Only 40% of CAPs provided proposed corrective actions that matched the reasons given for slow accrual. Seventy percent of trials were closed to accrual at time of analysis (phase I = 48; phase II = 46). Of these, 67% of phase I and 70% of phase II trials met their primary objectives, but they were active three times longer than projected. Among closed trials, 24% had an accrual rate increase associated with a greater likelihood of meeting their primary scientific objectives. Ultimately, trials receiving CAPs saw improved accrual rates. Future trials may benefit from implementing CAPs early in trial life cycles, but it may be more beneficial to invest in earlier accrual planning. Clin Cancer Res; 22(22); 5408-16. ©2016 AACRSee related commentary by Mileham and Kim, p. 5397. ©2016 American Association for Cancer Research.

Microchannel plate special nuclear materials sensor

NASA Astrophysics Data System (ADS)

Feller, W. B.; White, P. L.; White, P. B.; Siegmund, O. H. W.; Martin, A. P.; Vallerga, J. V.

2011-10-01

Nova Scientific Inc., is developing for the Domestic Nuclear Detection Office (DNDO SBIR #HSHQDC-08-C-00190), a solid-state, high-efficiency neutron detection alternative to 3He gas tubes, using neutron-sensitive microchannel plates (MCPs) containing 10B and/or Gd. This work directly supports DNDO development of technologies designed to detect and interdict nuclear weapons or illicit nuclear materials. Neutron-sensitized MCPs have been shown theoretically and more recently experimentally, to be capable of thermal neutron detection efficiencies equivalent to 3He gas tubes. Although typical solid-state neutron detectors typically have an intrinsic gamma sensitivity orders of magnitude higher than that of 3He gas detectors, we dramatically reduce gamma sensitivity by combining a novel electronic coincidence rejection scheme, employing a separate but enveloping gamma scintillator. This has already resulted in a measured gamma rejection ratio equal to a small 3He tube, without in principle sacrificing neutron detection efficiency. Ongoing improvements to the MCP performance as well as the coincidence counting geometry will be described. Repeated testing and validation with a 252Cf source has been underway throughout the Phase II SBIR program, with ongoing comparisons to a small commercial 3He gas tube. Finally, further component improvements and efforts toward integration maturity are underway, with the goal of establishing functional prototypes for SNM field testing.

Role of chemotherapy and targeted therapy in early-stage non-small cell lung cancer.

PubMed

Nagasaka, Misako; Gadgeel, Shirish M

2018-01-01

Adjuvant platinum based chemotherapy is accepted as standard of care in stage II and III non-small cell lung cancer (NSCLC) patients and is often considered in patients with stage IB disease who have tumors ≥ 4 cm. The survival advantage is modest with approximately 5% at 5 years. Areas covered: This review article presents relevant data regarding chemotherapy use in the perioperative setting for early stage NSCLC. A literature search was performed utilizing PubMed as well as clinical trial.gov. Randomized phase III studies in this setting including adjuvant and neoadjuvant use of chemotherapy as well as ongoing trials on targeted therapy and immunotherapy are also discussed. Expert commentary: With increasing utilization of screening computed tomography scans, it is possible that the percentage of early stage NSCLC patients will increase in the coming years. Benefits of adjuvant chemotherapy in early stage NSCLC patients remain modest. There is a need to better define patients most likely to derive survival benefit from adjuvant therapy and spare patients who do not need adjuvant chemotherapy due to the toxicity of such therapy. Trials for adjuvant targeted therapy, including adjuvant EGFR-TKI trials and trials of immunotherapy drugs are ongoing and will define the role of these agents as adjuvant therapy.

New Therapeutic Targets in Idiopathic Pulmonary Fibrosis. Aiming to Rein in Runaway Wound-Healing Responses

PubMed Central

Ahluwalia, Neil; Shea, Barry S.

2014-01-01

Idiopathic pulmonary fibrosis (IPF) is a devastating disease, with a median survival as short as 3 years from the time of diagnosis and no pharmacological therapies yet approved by the U.S. Food and Drug Administration. To address the great unmet need for effective IPF therapy, a number of new drugs have recently been, or are now being, evaluated in clinical trials. The rationales for most of these therapeutic candidates are based on the current paradigm of IPF pathogenesis, in which recurrent injury to the alveolar epithelium is believed to drive aberrant wound healing responses, resulting in fibrosis rather than repair. Here we discuss drugs in recently completed or currently ongoing phase II and III IPF clinical trials in the context of their putative mechanisms of action and the aberrant repair processes they are believed to target: innate immune activation and polarization, fibroblast accumulation and myofibroblast differentiation, or extracellular matrix deposition and stiffening. Placed in this context, the positive results of recently completed trials of pirfenidone and nintedanib, and results that will come from ongoing trials of other agents, should provide valuable insights into the still-enigmatic pathogenesis of this disease, in addition to providing benefits to patients with IPF. PMID:25090037

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...

Predictors of cerebral microembolization during phased radiofrequency ablation of atrial fibrillation: role of the ongoing rhythm and the site of energy delivery.

PubMed

Nagy-Balo, Edina; Kiss, Alexandra; Condie, Catherine; Stewart, Mark; Edes, Istvan; Csanadi, Zoltan

2014-11-01

Pulmonary vein isolation with phased radiofrequency current and use of a pulmonary vein ablation catheter (PVAC) has recently been associated with a high incidence of clinically silent brain infarcts on diffusion-weighted magnetic resonance imaging, and a high microembolic signal (MES) count detected by transcranial Doppler. We investigated the potential effects of the ongoing rhythm and the target vein during energy delivery (ED) on MES generation during PVAC ablations. A total of 735 EDs during 48 PVAC ablations were analyzed. MES counts were recorded for each ED and time-stamped for correlation with the ongoing rhythm and the target vein for each ED. Significantly higher MES counts were observed during ablations of the left-sided as compared with the right-sided pulmonary veins (P = 0.0003). Similarly, higher MES counts were detected during EDs in atrial fibrillation as compared with sinus rhythm when the temperature was >56°C (P < 0.0001). The ongoing rhythm had no effect on the number of MESs at lower temperatures during ablation. Both the ongoing rhythm during ED and the site of ablation influence microembolus generation during PVAC ablation procedures. ©2014 Wiley Periodicals, Inc.

Neratinib for the treatment of HER2-positive early stage breast cancer.

PubMed

Echavarria, Isabel; López-Tarruella, Sara; Márquez-Rodas, Iván; Jerez, Yolanda; Martin, Miguel

2017-08-01

Despite the advances in the treatment of HER2-positive breast cancer, resistance to actual chemotherapeutic regimens eventually occurs. Neratinib, an orally available pan-inhibitor of the ERBB family, represents an interesting new option for early-stage HER2-positive breast cancer. Areas covered: In this article, the development of neratinib, with a special focus on its potential value in the treatment of early-stage HER2-positive breast cancer, has been reviewed. For this purpose, a literature search was conducted, including preclinical studies, early-phase trials in advanced cancer with neratinib in monotherapy and in combination, and phase II and large phase III trials in the early setting. Management of neratinib-induced toxicity, future perspectives for the drug, and ongoing trials are also discussed in this review. Expert commentary: Neratinib is emerging as a promising oral drug for the treatment of HER2-positive breast cancer. Although FDA and EMA approval is derived from the extended adjuvant treatment, this setting may not be the ideal scenario to obtain the beneficial effects of neratinib. Confirmatory data in the neoadjuvant setting and subgroup analysis from the ExTENET trial might bring some light into the best setting for neratinib therapy. Data from confirmatory trials in the metastatic setting are also required.

Gulf Coast Salt Domes geologic Area Characterization Report, East Texas Study Area. Volume II. Technical report. [Contains glossary of geological terms; Oakwood, Keechi, and Palestine domes

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

Not Available

1982-07-01

The East Texas Area Characterization Report (ACR) is a compilation of data gathered during the Area Characterization phase of the Department of Energy's National Waste Terminal Storage program in salt. The characterization of Gulf Coast Salt Domes as a potential site for storage of nuclear waste is an ongoing process. This report summarizes investigations covering an area of approximately 2590 km/sup 2/ (1000 mi/sup 2/). Data on Oakwood, Keechi, and Palestine Domes are given. Subsequent phases of the program will focus on smaller land areas and fewer specific salt domes, with progressively more detailed investigations, possibly culminating with a licensemore » application to the Nuclear Regulatory Commission. The data in this report are a result of drilling and sampling, geophysical and geologic field work, and intensive literature review. The ACR contains text discussing data usage, interpretations, results and conclusions based on available geologic and hydrologic data, and figures including diagrams showing data point locations, geologic and hydrologic maps, geologic cross sections, and other geologic and hydrologic information. An appendix contains raw data gathered during this phase of the project and used in the preparation of these reports.« less

Online Answers Dealing with the Internment of Japanese Americans during World War II

ERIC Educational Resources Information Center

Lazar, Alon; Hirsch, Tal Litvak

2017-01-01

The internment of Americans of Japanese descent during World War II lies at the heart of ongoing discussions in American social studies. We analyzed inputs of members of the Yahoo! Answers Q&A online community following students' questions dealing with differential treatment of Japanese and German and Italian American citizens during World War…

Arizona Road Weather Information System (RWIS) communications plan

DOT National Transportation Integrated Search

2003-04-01

There have been two implementations of Roadway Weather Information Systems in Arizona, known as RWIS Phase 0 and Phase 1. Each Phase has met with limited success and has on-going issues that need to be addressed before new RWIS sites are implemented....

Change of motion and localization of cholesterol molecule during L(alpha)-H(II) transition.

PubMed Central

Hayakawa, E; Naganuma, M; Mukasa, K; Shimozawa, T; Araiso, T

1998-01-01

Formation of the inverted hexagonal (H(II)) phase from the lamellar (L(alpha)) phase of bovine brain-extracted phosphatidylcholine (BBPC) and phosphatidylethanolamine (BBPE) was investigated using 31P-NMR with or without cholesterol. When the ratio of BBPC to BBPE was 1:1, the H(II) formation was observed in the presence of 33 mol% cholesterol (i.e., BBPC:BBPE:cholesterol = 1:1:1) at 47 degrees C. The fraction of the H(II) phase in the BBPC/BBPE/cholesterol system could be controlled by the addition of dioleoylglycerol. The change of molecular motion of cholesterol affected by the H(II) formation was measured at various ratios of the L(alpha) to H(II) phase with the time-resolved fluorescence depolarization method, using dehydroergosterol as a fluorescent probe. It is observed that the motion of cholesterol became vigorous in the mixture state of the L(alpha) and the H(II) phases compared to that in the L(alpha) or the H(II) phase only. These facts show that cholesterol has the strong ability to induce the H(II) phase, probably by special molecular motion, which includes change of its location from the headgroup area to the acyl-chain area. PMID:9533700

Flight Test of the F/A-18 Active Aeroelastic Wing Airplane

NASA Technical Reports Server (NTRS)

Voracek, David

2007-01-01

A viewgraph presentation of flight tests performed on the F/A active aeroelastic wing airplane is shown. The topics include: 1) F/A-18 AAW Airplane; 2) F/A-18 AAW Control Surfaces; 3) Flight Test Background; 4) Roll Control Effectiveness Regions; 5) AAW Design Test Points; 6) AAW Phase I Test Maneuvers; 7) OBES Pitch Doublets; 8) OBES Roll Doublets; 9) AAW Aileron Flexibility; 10) Phase I - Lessons Learned; 11) Control Law Development and Verification & Validation Testing; 12) AAW Phase II RFCS Envelopes; 13) AAW 1-g Phase II Flight Test; 14) Region I - Subsonic 1-g Rolls; 15) Region I - Subsonic 1-g 360 Roll; 16) Region II - Supersonic 1-g Rolls; 17) Region II - Supersonic 1-g 360 Roll; 18) Region III - Subsonic 1-g Rolls; 19) Roll Axis HOS/LOS Comparison Region II - Supersonic (open-loop); 20) Roll Axis HOS/LOS Comparison Region II - Supersonic (closed-loop); 21) AAW Phase II Elevated-g Flight Test; 22) Region I - Subsonic 4-g RPO; and 23) Phase II - Lessons Learned

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

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

[Effect of different nutritional support on pancreatic secretion in acute pancreatitis].

PubMed

Achkasov, E E; Pugaev, A V; Nabiyeva, Zh G; Kalachev, S V

To develop and justify optimal nutritional support in early phase of acute pancreatitis (AP). 140 AP patients were enrolled. They were divided into groups depending on nutritional support: group I (n=70) - early enteral tube feeding (ETF) with balanced mixtures, group II (n=30) - early ETF with oligopeptide mixture, group III (n=40) - total parenteral nutrition (TPN). The subgroups were also isolated depending on medication: A - Octreotide, B - Quamatel, C - Octreotide + Quamatel. Pancreatic secretion was evaluated by using of course of disease, instrumental methods, APUD-system hormone levels (secretin, cholecystokinin, somatostatin, vasointestinal peptide). ETF was followed by pancreas enlargement despite ongoing therapy, while TPN led to gradual reduction of pancreatic size up to normal values. α-amylase level progressively decreased in all groups, however in patients who underwent ETF (I and II) mean values of the enzyme were significantly higher compared with TPN (group III). Secretin, cholecystokinin and vasointestinal peptide were increasing in most cases, while the level of somatostatin was below normal in all groups. Enteral tube feeding (balanced and oligopeptide mixtures) contributes to pancreatic secretion compared with TPN, but this negative impact is eliminated by antisecretory therapy. Dual medication (Octreotide + Quamatel) is more preferable than monotherapy (Octreotide or Quamatel).

Oral Sulforaphane increases Phase II antioxidant enzymes in the human upper airway

PubMed Central

Riedl, Marc A.; Saxon, Andrew; Diaz-Sanchez, David

2009-01-01

Background Cellular oxidative stress is an important factor in asthma and is thought to be the principle mechanism by which oxidant pollutants such as ozone and particulates mediate their pro-inflammatory effects. Endogenous Phase II enzymes abrogate oxidative stress through the scavenging of reactive oxygen species and metabolism of reactive chemicals. Objective We conducted a placebo-controlled dose escalation trial to investigate the in vivo effects of sulforaphane, a naturally occurring potent inducer of Phase II enzymes, on the expression of glutathione-s-transferase M1 (GSTM1), glutathione-s-transferase P1 (GSTP1), NADPH quinone oxidoreductase (NQO1), and hemoxygenase-1 (HO-1) in the upper airway of human subjects. Methods Study subjects consumed oral sulforaphane doses contained in a standardized broccoli sprout homogenate (BSH). RNA expression for selected Phase II enzymes was measured in nasal lavage cells by RT-PCR before and after sulforaphane dosing. Results All subjects tolerated oral sulforaphane dosing without significant adverse events. Increased Phase II enzyme expression in nasal lavage cells occurred in a dose-dependent manner with maximal enzyme induction observed at the highest dose of 200 grams broccoli sprouts prepared as BSH. Significant increases were seen in all sentinel Phase II enzymes RNA expression compared to baseline. Phase II enzyme induction was not seen with ingestion of non-sulforaphane containing alfalfa sprouts. Conclusion Oral sulforaphane safely and effectively induces mucosal Phase II enzyme expression in the upper airway of human subjects. This study demonstrates the potential of antioxidant Phase II enzymes induction in the human airway as a strategy to reduce the inflammatory effects of oxidative stress. Clinical Implications This study demonstrates the potential of enhancement of Phase II enzyme expression as a novel therapeutic strategy for oxidant induced airway disease. Capsule Summary A placebo-controlled dose escalation trial demonstrated that naturally occurring sulforaphane from broccoli sprouts can induce a potent increase in antioxidant Phase II enzymes in airway cells. PMID:19028145

Centrifuge workers study. Phase II, completion report

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

Wooten, H.D.

1994-09-01

Phase II of the Centrifuge Workers Study was a follow-up to the Phase I efforts. The Phase I results had indicated a higher risk than expected among centrifuge workers for developing bladder cancer when compared with the risk in the general population for developing this same type of cancer. However, no specific agent could be identified as the causative agent for these bladder cancers. As the Phase II Report states, Phase I had been limited to workers who had the greatest potential for exposure to substances used in the centrifuge process. Phase II was designed to expand the survey tomore » evaluate the health of all employees who had ever worked in Centrifuge Program Departments 1330-1339 but who had not been interviewed in Phase I. Employees in analytical laboratories and maintenance departments who provided support services for the Centrifuge Program were also included in Phase II. In December 1989, the Oak Ridge Associated Universities (ORAU), now known as Oak Ridge Institute for Science and Education (ORISE), was contracted to conduct a follow-up study (Phase II). Phase H of the Centrifuge Workers Study expanded the survey to include all former centrifuge workers who were not included in Phase I. ORISE was chosen because they had performed the Phase I tasks and summarized the corresponding survey data therefrom.« less

The MUK five protocol: a phase II randomised, controlled, parallel group, multi-centre trial of carfilzomib, cyclophosphamide and dexamethasone (CCD) vs. cyclophosphamide, bortezomib (Velcade) and dexamethasone (CVD) for first relapse and primary refractory multiple myeloma.

PubMed

Brown, Sarah; Hinsley, Samantha; Ballesteros, Mónica; Bourne, Sue; McGarry, Paul; Sherratt, Debbie; Flanagan, Louise; Gregory, Walter; Cavenagh, Jamie; Owen, Roger; Williams, Cathy; Kaiser, Martin; Low, Eric; Yong, Kwee

2016-01-01

Multiple myeloma is a plasma cell tumour with an annual incidence in the UK of approximately 40-50 per million i.e. about 4500 new cases per annum. The triple combination cyclophosphamide, bortezomib (Velcade®) and dexamethasone (CVD) is an effective regimen at relapse and has emerged in recent years as the standard therapy at first relapse in the UK. Carfilzomib has good activity as a single agent in the relapsed setting, and it is expected that efficacy will be improved when used in combination with dexamethasone and cyclophosphamide. MUK Five is a phase II open label, randomised, controlled, parallel group, multi-centre trial that will compare the activity of carfilzomib, cyclophosphamide and dexamethasone (CCD) with that of CVD, given over an equivalent treatment period (24 weeks), in participants with multiple myeloma at first relapse, or refractory to no more than 1 line of treatment. In addition, the study also aims to assess the utility of a maintenance schedule of carfilzomib in these participants. The primary objective of the trial is to assess whether CCD provides non-inferior activity in terms of ≥ VGPR rates at 24 weeks, and whether the addition of maintenance treatment with carfilzomib to CCD provides superior activity in terms of progression-free survival, as compared to CCD with no maintenance. Secondary objectives include comparing toxicity profiles, further summarizing and comparing the activity of the different treatment arms and analysis of the effect of each treatment arm on minimal residual disease status. The development of carfilzomib offers the opportunity to further explore the anti-tumour efficacy of proteasome inhibition and, based on the available evidence, it is important and timely to obtain data on the activity, toxicity and tolerability of this drug. In contrast to ongoing phase III trials, this phase II trial has a unique subset of participants diagnosed with multiple myeloma at first relapse or refractory to no more than 1 line of treatment and will also evaluate the utility of maintenance with carfilzomib for up to 18 months and investigate minimal residual disease status to provide information on depth of response and the prognostic impact thereof. The trial is registered under ISRCTN17354232, December 2012.

Converging Redundant Sensor Network Information for Improved Building Control

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

Dale Tiller; D. Phil; Gregor Henze

2007-09-30

This project investigated the development and application of sensor networks to enhance building energy management and security. Commercial, industrial and residential buildings often incorporate systems used to determine occupancy, but current sensor technology and control algorithms limit the effectiveness of these systems. For example, most of these systems rely on single monitoring points to detect occupancy, when more than one monitoring point could improve system performance. Phase I of the project focused on instrumentation and data collection. During the initial project phase, a new occupancy detection system was developed, commissioned and installed in a sample of private offices and open-planmore » office workstations. Data acquisition systems were developed and deployed to collect data on space occupancy profiles. Phase II of the project demonstrated that a network of several sensors provides a more accurate measure of occupancy than is possible using systems based on single monitoring points. This phase also established that analysis algorithms could be applied to the sensor network data stream to improve the accuracy of system performance in energy management and security applications. In Phase III of the project, the sensor network from Phase I was complemented by a control strategy developed based on the results from the first two project phases: this controller was implemented in a small sample of work areas, and applied to lighting control. Two additional technologies were developed in the course of completing the project. A prototype web-based display that portrays the current status of each detector in a sensor network monitoring building occupancy was designed and implemented. A new capability that enables occupancy sensors in a sensor network to dynamically set the 'time delay' interval based on ongoing occupant behavior in the space was also designed and implemented.« less

Liraglutide efficacy and action in non-alcoholic steatohepatitis (LEAN): study protocol for a phase II multicentre, double-blinded, randomised, controlled trial

PubMed Central

Armstrong, Matthew J; Barton, Darren; Gaunt, Piers; Hull, Diana; Guo, Kathy; Stocken, Deborah; Gough, Stephen C L; Tomlinson, Jeremy W; Brown, Rachel M; Hübscher, Stefan G; Newsome, Philip N

2013-01-01

Introduction Non-alcoholic steatohepatitis (NASH) is now the commonest cause of chronic liver disease. Despite this, there are no universally accepted pharmacological therapies for NASH. Liraglutide (Victoza), a human glucagon-like peptide-1 (GLP-1) analogue, has been shown to improve weight loss, glycaemic control and liver enzymes in type 2 diabetes. There is currently a lack of prospective-controlled studies investigating the efficacy of GLP-1 analogues in patients with NASH. Methods and analysis Liraglutide efficacy and action in NASH (LEAN) is a phase II, multicentre, double-blinded, placebo-controlled, randomised clinical trial designed to investigate whether a 48-week treatment with 1.8 mg liraglutide will result in improvements in liver histology in patients with NASH. Adult, overweight (body mass index ≥25 kg/m2) patients with biopsy-confirmed NASH were assessed for eligibility at five recruitment centres in the UK. Patients who satisfied the eligibility criteria were randomly assigned (1:1) to receive once-daily subcutaneous injections of either 1.8 mg liraglutide or liraglutide-placebo (control). Using A'Hern's single stage phase II methodology (significance level 0.05; power 0.90) and accounting for an estimated 20% withdrawal rate, a minimum of 25 patients were randomised to each treatment group. The primary outcome measure will be centrally assessed using an intention-to-treat analysis of the proportion of evaluable patients achieving an improvement in liver histology between liver biopsies at baseline and after 48 weeks of treatment. Histological improvement will be defined as a combination of the disappearance of active NASH and no worsening in fibrosis. Ethics and dissemination The protocol was approved by the National Research Ethics Service (East Midlands—Northampton committee; 10/H0402/32) and the Medicines and Healthcare products Regulatory Agency. Recruitment into the LEAN started in August 2010 and ended in May 2013, with 52 patients randomised. The treatment follow-up of LEAN participants is currently ongoing and is due to finish in July 2014. The findings of this trial will be disseminated through peer-reviewed publications and international presentations. Trial registration clinicaltrials.gov NCT01237119. PMID:24189085

Microbial Community Phylogenetic and Functional Succession in Chromium-Reducing Aquifer-Derived Microcosms

NASA Astrophysics Data System (ADS)

Brodie, E. L.; Beller, H. R.; Goldfarb, K. C.; Han, R.; Santee, C. A.

2009-12-01

In situ reductive immobilization, whereby highly soluble Cr(VI) species are reduced to poorly soluble Cr(III) species, is a favored approach for remediating Cr-contaminated groundwater. How microbial populations respond phylogenetically and functionally to the injection of an organic electron donor to stimulate Cr(VI) reduction is unclear, as are the relative contributions of direct enzymatic Cr(VI) reduction versus indirect (e.g. sulfide-mediated) reduction. In this study, we inoculated anaerobic microcosms with groundwater from the Cr-contaminated Hanford 100H site (WA) and supplemented them with lactate and the electron acceptors nitrate, sulfate, and amorphous ferric oxyhydroxide. The microcosms progressed successively through nitrate-reducing, sulfate-reducing, and Fe(III)-reducing conditions, and after a second nitrate amendment, nitrate-dependent Fe(II)-oxidizing conditions. Cr(VI) reduction occurred during both the denitrification and the sulfate/iron reduction phases. DNA and RNA were harvested during each major biogeochemical phase and were subjected to PhyloChip analysis, qPCR, and transcript sequencing. Bacterial community succession followed a trajectory related to the sequential use of electron acceptors. During denitrification, bacterial communities were enriched in known denitrifiers within the Beta- and Gamma-proteobacteria and became phylogenetically clustered. Fermenters became enriched following nitrate reduction, preceding both iron and sulfate reduction. Iron reduction was stoichiometrically related to the formation of hydrogen sulfide and, although iron reducers were detected during this phase, their iron-reducing activity was not confirmed. Following the depletion of lactate and sulfate, iron reduction rates decreased and acetate and propionate concentrations stabilized, indicating a marginal contribution of acetate-coupled iron reduction. Rapid Fe(II) oxidation occurred following the nitrate amendment with a concomitant reduction of nitrate to nitrite and an increased abundance of Beta-proteobacterial species related to known anaerobic Fe(II)-oxidizing bacteria. To uncover the microbial mechanisms contributing to the biogeochemical complexity encountered, even under controlled laboratory incubations, requires alternatives to standard phylogenetic analyses. Our ongoing efforts in analyzing the community transcriptomes (mRNA) should provide valuable insight into the relative rates of direct versus indirect mechanisms of Cr(VI) immobilization in contaminated aquifers.

A subsurface Fe-silicate weathering microbiome

NASA Astrophysics Data System (ADS)

Napieralski, S. A.; Buss, H. L.; Roden, E. E.

2017-12-01

Traditional models of microbially mediated weathering of primary Fe-bearing minerals often invoke organic ligands (e.g. siderophores) used for nutrient acquisition. However, it is well known that the oxidation of Fe(II) governs the overall rate of Fe-silicate mineral dissolution. Recent work has demonstrated the ability of lithtrophic iron oxidizing bacteria (FeOB) to grow via the oxidation of structural Fe(II) in biotite as a source of metabolic energy with evidence suggesting a direct enzymatic attack on the mineral surface. This process necessitates the involvement of dedicated outer membrane proteins that interact with insoluble mineral phases in a process known as extracellular electron transfer (EET). To investigate the potential role FeOB in a terrestrial subsurface weathering system, samples were obtained from the bedrock-saprolite interface (785 cm depth) within the Rio Icacos Watershed of the Luquillo Mountains in Puerto Rico. Prior geochemical evidence suggests the flux of Fe(II) from the weathering bedrock supports a robust lithotrophic microbial community at depth. Current work confirms the activity of microorganism in situ, with a marked increase in ATP near the bedrock-saprolite interface. Regolith recovered from the interface was used as inoculum to establish enrichment cultures with powderized Fe(II)-bearing minerals serving as the sole energy source. Monitoring of the Fe(II)/Fe(total) ratio and ATP generation suggests growth of microorganisms coupled to the oxidation of mineral bound Fe(II). Analysis of 16S rRNA gene and shotgun metagenomic libraries from in situ and enrichment culture samples lends further support to FeOB involvement in the weathering process. Multiple metagenomic bins related to known FeOB, including Betaproteobacteria genera, contain homologs to model EET systems, including Cyc2 and MtoAB. Our approach combining geochemistry and metagenomics with ongoing microbiological and genomic characterization of novel isolates obtained from enrichment cultures provides insight into the role of FeOB in Fe(II)-mineral alteration as well as furthering our understanding of the biotic reactions contributing the globally important biogeochemical phenomenon of chemical weathering.

Design of Concurrency Controls for Transaction Processing Systems.

DTIC Science & Technology

1982-04-02

presented in numerous textbooks (e.g.; see [Wiederhold 771, [Date 77), or [Ulman 80]) and elsewhere; furthermore, this is a problem of on-going research...bIA (tem -II am&p Ilest WI: m9 bme "" from Mt: (mew imew) (enter -eow (en Smemp) am :es. daeems:m W4 (saw. mumv Ibe o O*jeets Ai Daiua* II Suomi -ov

Space Acceleration Measurement System-II

NASA Technical Reports Server (NTRS)

Foster, William

2009-01-01

Space Acceleration Measurement System (SAMS-II) is an ongoing study of the small forces (vibrations and accelerations) on the ISS that result from the operation of hardware, crew activities, as well as dockings and maneuvering. Results will be used to generalize the types of vibrations affecting vibration-sensitive experiments. Investigators seek to better understand the vibration environment on the space station to enable future research.

TES-Based Light Detectors for the CRESST Direct Dark Matter Search

NASA Astrophysics Data System (ADS)

Rothe, J.; Angloher, G.; Bauer, P.; Bento, A.; Bucci, C.; Canonica, L.; D'Addabbo, A.; Defay, X.; Erb, A.; Feilitzsch, F. v.; Ferreiro Iachellini, N.; Gorla, P.; Gütlein, A.; Hauff, D.; Jochum, J.; Kiefer, M.; Kluck, H.; Kraus, H.; Lanfranchi, J.-C.; Langenkämper, A.; Loebell, J.; Mancuso, M.; Mondragon, E.; Münster, A.; Pagliarone, C.; Petricca, F.; Potzel, W.; Pröbst, F.; Puig, R.; Reindl, F.; Schäffner, K.; Schieck, J.; Schipperges, V.; Schönert, S.; Seidel, W.; Stahlberg, M.; Stodolsky, L.; Strandhagen, C.; Strauss, R.; Tanzke, A.; Trinh Thi, H. H.; Türkoğlu, C.; Ulrich, A.; Usherov, I.; Wawoczny, S.; Willers, M.; Wüstrich, M.

2018-05-01

The CRESST experiment uses cryogenic detectors based on transition-edge sensors to search for dark matter interactions. Each detector module consists of a scintillating CaWO_4 crystal and a silicon-on-sapphire (SOS) light detector which operate in coincidence (phonon-light technique). The 40-mm-diameter SOS disks (2 g mass) used in the data taking campaign of CRESST-II Phase 2 (2014-2016) reached absolute baseline resolutions of σ = 4-7 eV. This is the best performance reported for cryogenic light detectors of this size. Newly developed silicon beaker light detectors (4 cm height, 4 cm diameter, 6 g mass), which cover a large fraction of the target crystal surface, have achieved a baseline resolution of σ = 5.8 eV. First results of further improved light detectors developed for the ongoing low-threshold CRESST-III experiment are presented.

Multipurpose Wetlands Phase II/III: final design and ongoing research investigations

USGS Publications Warehouse

Babbitt, Bruce; Beard, Daniel P.; Hancock, Lawrence F.

1994-01-01

The Eastern Municipal Water District (EMWD), the Bureau of Reclamation (USBR), and the National Biological Survey (NBS), in consultation with other governmental agencies, the academic community, and environmental groups, are involved in a cooperative wetlands research and demonstration effort. This report reflects progress through the first 3 years of a 5-year program. The goal of the Multipurpose Wetlands Research and Demonstration Project is to evaluate and expand the use of reclaimed water and contaminated ground water through the incorporation of multipurpose constructed wetlands into EMWD's total water resources management program. The focus of the wetlands is the development of design, construction, and operation criteria that will provide a cost-effective and innovative alternative for managing water resources and provide other public benefits in arid areas. The program also recognizes the fact that naturally-occurring wetlands, both coastal and inland, have been disappearing at an alarming rate.

Circulating tumor cells: clinical validity and utility.

PubMed

Cabel, Luc; Proudhon, Charlotte; Gortais, Hugo; Loirat, Delphine; Coussy, Florence; Pierga, Jean-Yves; Bidard, François-Clément

2017-06-01

Circulating tumor cells (CTCs) are rare tumor cells and have been investigated as diagnostic, prognostic and predictive biomarkers in many types of cancer. Although CTCs are not currently used in clinical practice, CTC studies have accumulated a high level of clinical validity, especially in breast, lung, prostate and colorectal cancers. In this review, we present an overview of the current clinical validity of CTCs in metastatic and non-metastatic disease, and the main concepts and studies investigating the clinical utility of CTCs. In particular, this review will focus on breast, lung, colorectal and prostate cancer. Three major topics concerning the clinical utility of CTC are discussed-(1) treatment based on CTCs used as liquid biopsy, (2) treatment based on CTC count or CTC variations, and (3) treatment based on CTC biomarker expression. A summary of published or ongoing phase II and III trials is also presented.

78 FR 13344 - Agency Forms Undergoing Paperwork Reduction Act Review

Federal Register 2010, 2011, 2012, 2013, 2014

2013-02-27

... an ongoing manner, most of the more than 4,500 hospitals now reporting to the CDC's current HAI... acute care hospitals in one U.S. city. This pilot phase was followed in 2010 by a phase 2, limited roll..., Minnesota, New Mexico, New York, Oregon, and Tennessee). Experience gained in the phase 1 and phase 2...

A phased array bread board for future remote sensing applications

NASA Astrophysics Data System (ADS)

Zahn, R. W.; Schmidt, E.

The next generation of SAR antennas will be of the active phased-array type. The ongoing development of a phased-array breadboard for remote sensing is described. Starting from a detailed system design, a functional representative breadboard was developed. The design and the performance of the breadboard are discussed.

Guidelines for Adolescent Depression in Primary Care (GLAD-PC): Part II. Treatment and Ongoing Management.

PubMed

Cheung, Amy H; Zuckerbrot, Rachel A; Jensen, Peter S; Laraque, Danielle; Stein, Ruth E K

2018-02-26

To update clinical practice guidelines to assist primary care (PC) in the screening and assessment of depression. In this second part of the updated guidelines, we address treatment and ongoing management of adolescent depression in the PC setting. By using a combination of evidence- and consensus-based methodologies, the guidelines were updated in 2 phases as informed by (1) current scientific evidence (published and unpublished) and (2) revision and iteration among the steering committee, including youth and families with lived experience. These updated guidelines are targeted for youth aged 10 to 21 years and offer recommendations for the management of adolescent depression in PC, including (1) active monitoring of mildly depressed youth, (2) treatment with evidence-based medication and psychotherapeutic approaches in cases of moderate and/or severe depression, (3) close monitoring of side effects, (4) consultation and comanagement of care with mental health specialists, (5) ongoing tracking of outcomes, and (6) specific steps to be taken in instances of partial or no improvement after an initial treatment has begun. The strength of each recommendation and the grade of its evidence base are summarized. The Guidelines for Adolescent Depression in Primary Care cannot replace clinical judgment, and they should not be the sole source of guidance for adolescent depression management. Nonetheless, the guidelines may assist PC clinicians in the management of depressed adolescents in an era of great clinical need and a shortage of mental health specialists. Additional research concerning the management of depressed youth in PC is needed, including the usability, feasibility, and sustainability of guidelines, and determination of the extent to which the guidelines actually improve outcomes of depressed youth. Copyright © 2018 by the American Academy of Pediatrics.

47 CFR 69.727 - Regulatory relief.

Code of Federal Regulations, 2010 CFR

2010-10-01

... customer. (b) Phase II relief. Upon satisfaction of the Phase II triggers specified in §§ 69.709(c) or 69... Pricing Flexibility § 69.727 Regulatory relief. (a) Phase I relief. Upon satisfaction of the Phase I... similarly situated customers; and (ii) The price cap LEC excludes all contract tariff offerings from price...

47 CFR 90.769 - Construction and implementation of Phase II nationwide licenses.

Code of Federal Regulations, 2011 CFR

2011-10-01

... Use of Frequencies in the 220-222 MHz Band Policies Governing the Licensing and Use of Phase II Ea, Regional and Nationwide Systems § 90.769 Construction and implementation of Phase II nationwide licenses...

Barriers to participation in a phase II cardiac rehabilitation programme.

PubMed

Mak, Y M W; Chan, W K; Yue, C S S

2005-12-01

To identify barriers to participation in a phase II cardiac rehabilitation programme and measures that may enhance participation. Prospective study. Regional hospital, Hong Kong. Cardiac patients recruited for a phase I cardiac rehabilitation programme from July 2002 to January 2003. Reasons for not participating in a phase II cardiac rehabilitation programme. Of the 193 patients recruited for a phase I cardiac rehabilitation programme, 152 (79%) patients, with a mean age of 70.3 years (standard deviation, 11.9 years), did not proceed to phase II programme. Eleven (7%) deaths occurred before commencement of phase II and 74 (49%) patients were considered physically unfit. Reasons for the latter included fractures, pain, or degenerative changes in the lower limbs (24%), and co-morbidities such as cerebrovascular accident (19%), chronic renal failure (11%), congestive heart failure (9%), and unstable angina (8%). Phase II rehabilitation was postponed until after completion of scheduled cardiac interventions in 13% of patients. Failure of physicians to arrange the pre-phase II exercise stress test as per protocol was reported in 7% of patients. Other reasons were reported: work or time conflicts (16%), non-compliance with cardiac treatment (5%), financial constraints (4%), self-exercise (3%), fear after exercise stress testing (3%), and patients returning to their original cardiologists for treatment (3%). A significant (79%) proportion of patients did not proceed to a phase II cardiac rehabilitation programme for a variety of reasons. These included physical unfitness, work or time conflicts, and need to attend scheduled cardiac interventions. Further studies are required to determine how to overcome obstacles to cardiac rehabilitation.

Discovery and clinical introduction of first-in-class imipridone ONC201.

PubMed

Allen, Joshua E; Kline, C Leah B; Prabhu, Varun V; Wagner, Jessica; Ishizawa, Jo; Madhukar, Neel; Lev, Avital; Baumeister, Marie; Zhou, Lanlan; Lulla, Amriti; Stogniew, Martin; Schalop, Lee; Benes, Cyril; Kaufman, Howard L; Pottorf, Richard S; Nallaganchu, B Rao; Olson, Gary L; Al-Mulla, Fahd; Duvic, Madeleine; Wu, Gen Sheng; Dicker, David T; Talekar, Mala K; Lim, Bora; Elemento, Olivier; Oster, Wolfgang; Bertino, Joseph; Flaherty, Keith; Wang, Michael L; Borthakur, Gautam; Andreeff, Michael; Stein, Mark; El-Deiry, Wafik S

2016-11-08

ONC201 is the founding member of a novel class of anti-cancer compounds called imipridones that is currently in Phase II clinical trials in multiple advanced cancers. Since the discovery of ONC201 as a p53-independent inducer of TRAIL gene transcription, preclinical studies have determined that ONC201 has anti-proliferative and pro-apoptotic effects against a broad range of tumor cells but not normal cells. The mechanism of action of ONC201 involves engagement of PERK-independent activation of the integrated stress response, leading to tumor upregulation of DR5 and dual Akt/ERK inactivation, and consequent Foxo3a activation leading to upregulation of the death ligand TRAIL. ONC201 is orally active with infrequent dosing in animals models, causes sustained pharmacodynamic effects, and is not genotoxic. The first-in-human clinical trial of ONC201 in advanced aggressive refractory solid tumors confirmed that ONC201 is exceptionally well-tolerated and established the recommended phase II dose of 625 mg administered orally every three weeks defined by drug exposure comparable to efficacious levels in preclinical models. Clinical trials are evaluating the single agent efficacy of ONC201 in multiple solid tumors and hematological malignancies and exploring alternative dosing regimens. In addition, chemical analogs that have shown promise in other oncology indications are in pre-clinical development. In summary, the imipridone family that comprises ONC201 and its chemical analogs represent a new class of anti-cancer therapy with a unique mechanism of action being translated in ongoing clinical trials.

Discovery and clinical introduction of first-in-class imipridone ONC201

PubMed Central

Allen, Joshua E.; Kline, C. Leah B.; Prabhu, Varun V.; Wagner, Jessica; Ishizawa, Jo; Madhukar, Neel; Lev, Avital; Baumeister, Marie; Zhou, Lanlan; Lulla, Amriti; Stogniew, Martin; Schalop, Lee; Benes, Cyril; Kaufman, Howard L.; Pottorf, Richard S.; Nallaganchu, B. Rao; Olson, Gary L.; Al-Mulla, Fahd; Duvic, Madeleine; Wu, Gen Sheng; Dicker, David T.; Talekar, Mala K.; Lim, Bora; Elemento, Olivier; Oster, Wolfgang; Bertino, Joseph; Flaherty, Keith; Wang, Michael L.; Borthakur, Gautam; Andreeff, Michael; Stein, Mark; El-Deiry, Wafik S.

2016-01-01

ONC201 is the founding member of a novel class of anti-cancer compounds called imipridones that is currently in Phase II clinical trials in multiple advanced cancers. Since the discovery of ONC201 as a p53-independent inducer of TRAIL gene transcription, preclinical studies have determined that ONC201 has anti-proliferative and pro-apoptotic effects against a broad range of tumor cells but not normal cells. The mechanism of action of ONC201 involves engagement of PERK-independent activation of the integrated stress response, leading to tumor upregulation of DR5 and dual Akt/ERK inactivation, and consequent Foxo3a activation leading to upregulation of the death ligand TRAIL. ONC201 is orally active with infrequent dosing in animals models, causes sustained pharmacodynamic effects, and is not genotoxic. The first-in-human clinical trial of ONC201 in advanced aggressive refractory solid tumors confirmed that ONC201 is exceptionally well-tolerated and established the recommended phase II dose of 625 mg administered orally every three weeks defined by drug exposure comparable to efficacious levels in preclinical models. Clinical trials are evaluating the single agent efficacy of ONC201 in multiple solid tumors and hematological malignancies and exploring alternative dosing regimens. In addition, chemical analogs that have shown promise in other oncology indications are in pre-clinical development. In summary, the imipridone family that comprises ONC201 and its chemical analogs represent a new class of anti-cancer therapy with a unique mechanism of action being translated in ongoing clinical trials. PMID:27602582

Studies of Methane Counterflow Flames at Low Pressures

NASA Astrophysics Data System (ADS)

Burrell, Robert Roe

Methane is the smallest hydrocarbon molecule, the fuel most widely studied in fundamental flame structure studies, and a major component of natural gas. Despite many decades of research into the fundamental chemical kinetics involved in methane oxidation, ongoing advancements in research suggest that more progress can be made. Though practical combustors of industrial and commercial significance operate at high pressures and turbulent flow conditions, fundamental understanding of combustion chemistry in flames is more readily obtained for low pressure and laminar flow conditions. Measurements were performed from 1 to 0.1 atmospheres for premixed methane/air and non-premixed methane-nitrogen/oxygen flames in a counterflow. Comparative modeling with quasi-one-dimensional strained flame codes revealed bias-induced errors in measured velocities up to 8% at 0.1 atmospheres due to tracer particle phase velocity slip in the low density gas reacting flow. To address this, a numerically-assisted correction scheme consisting of direct simulation of the particle phase dynamics in counterflow was implemented. Addition of reactions describing the prompt dissociation of formyl radicals to an otherwise unmodified USC Mech II kinetic model was found to enhance computed flame reactivity and substantially improve the predictive capability of computed results for measurements at the lowest pressures studied. Yet, the same modifications lead to overprediction of flame data at 1 atmosphere where results from the unmodified USC Mech II kinetic mechanism agreed well with ambient pressure flame data. The apparent failure of a single kinetic model to capture pressure dependence in methane flames motivates continued skepticism regarding the current understanding of pressure dependence in kinetic models, even for the simplest fuels.

Paperless medical records: measuring success.

PubMed

Tobey, Mary Ellen

2004-01-01

North Shore Magnetic Imaging Center (NSMIC) underwent a major transformation of the patient process through an 18-month "Reinvention Project." The project began in October 2002, with an assessment of systems in place. A complete review of each stage of the patient process--scheduling, registration, insurance verification, screening, scanning, transcription, and billing--resulted in the discovery that the paperwork for a single patient examination could go though as many as 20 sets of hands. The project was supported by the formation of an internal team comprised of staff members from all departments (support, patient accounts, and technical), radiologists, and members of the center's senior management team. The team had 2 goals: increase the level of patient care, and create a paperless environment. External teams were formed to address specific areas targeted to support the process. The transformation for all involved--patients, staff, radiologists, and referring physicians--has proved to be very positive. The work, however, was not finished. Upon the project's completion, NSMIC recognized the importance of identifying successes and areas for improvement. These included ongoing reviews of the project's impact on all stakeholders and looking for new technologies and programs to enhance the new systems in place. There are plans for a project "sequel." Strategies are being developed for "Reinvention, Phase II." Elements of these strategies include enhancement of the scheduling programs to create more checks and balances for the staff and investigating an online scheduling option for the center's referring physicians. The purchase and implementation of a voice recognition system--tabled during Phase I--is scheduled for the first quarter of 2005.

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

PubMed

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

2015-12-10

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

Subliminal stimuli modulate somatosensory perception rhythmically and provide evidence for discrete perception.

PubMed

Baumgarten, Thomas J; Königs, Sara; Schnitzler, Alfons; Lange, Joachim

2017-03-09

Despite being experienced as continuous, there is an ongoing debate if perception is an intrinsically discrete process, with incoming sensory information treated as a succession of single perceptual cycles. Here, we provide causal evidence that somatosensory perception is composed of discrete perceptual cycles. We used in humans an electrotactile temporal discrimination task preceded by a subliminal (i.e., below perceptual threshold) stimulus. Although not consciously perceived, subliminal stimuli are known to elicit neuronal activity in early sensory areas and modulate the phase of ongoing neuronal oscillations. We hypothesized that the subliminal stimulus indirectly, but systematically modulates the ongoing oscillatory phase in S1, thereby rhythmically shaping perception. The present results confirm that, without being consciously perceived, the subliminal stimulus critically influenced perception in the discrimination task. Importantly, perception was modulated rhythmically, in cycles corresponding to the beta-band (13-18 Hz). This can be compellingly explained by a model of discrete perceptual cycles.

Sundstrand’s Precision Metal Forming Cell. Industrial Modernization Incentive Program (IMIP). Phase 2

DTIC Science & Technology

1991-03-01

1-2 1.4 CONCLUSIONS AND RECOMMENDATIONS ....................... 1-2 20. PHASE II MANAGEMENT PLAN...2-1 2.1 PROGRAM MANAGEMENT ................................... 2-1 2.2 IM IP TEAM...Barbier, reference Section 2.0 (Phase II Management Plan), is complete and this report provides the results of the Phase II study. 1.2 OBJECTIVES The

What Works in Oklahoma Schools: A Comprehensive Needs Assessment of Oklahoma Schools. Phase II State Report

ERIC Educational Resources Information Center

Marzano Research Laboratory, 2010

2010-01-01

Phase II provides a more detailed examination of classroom variables important to achievement in Oklahoma schools. Where Phase I addressed all nine of the Oklahoma essential elements using survey data, Phase II focuses on what occurs in Oklahoma classrooms primarily using data from principal interviews, classroom observations (on-site), and video…

Waging the War on Clinical Grade Inflation: The Ongoing Quest.

PubMed

Seldomridge, Lisa A; Walsh, Catherine M

This study examined the presence of grade inflation in clinical courses 9 years after implementing strategies to improve grading precision. A comparison of clinical grades for cohort I (1997-2002) with cohort II (2009-2016) showed statistically lower grades in 2 courses (Adult 1 and Maternity) for cohort II. Suggestions for changing the way clinical experiences are planned, executed, and evaluated are provided.

Smoking cessation intervention within the framework of a lung cancer screening program: preliminary results and clinical perspectives from the "Cosmos-II" Trial.

PubMed

Filippo, Lococo; Principe, Rosastella; Cesario, Alfredo; Apolone, Giovanni; Carleo, Francesco; Ialongo, Pasquale; Veronesi, Giulia; Cardillo, Giuseppe

2015-02-01

Data coming from the literature investigating the effectiveness and interaction between smoking cessation (SC) and lung cancer screening (LCScr) are still sparse and inconsistent. Herein, we report the preliminary results from the ongoing lung cancer screening trial ("Cosmos-II") focusing our analysis on the inter-relationship between the SC program and the LCScr.

Filgotinib for the treatment of Crohn's disease.

PubMed

Labetoulle, Remi; Paul, Stephane; Roblin, Xavier

2018-03-01

Inflammatory bowel diseases, such as Crohn's disease (CD) and ulcerative colitis (UC), are widespread diseases (with an estimated 2.2 million Europeans affected), and even populations previously considered 'low risk' (such as Japan and India) are witnessing an increasing incidence. CD is a chronic, progressive immunologically driven disease, with an evolution characterized by succession of periods of progression and remission. New physiopathological pathways are continuously being discovered, the more we understand about how the disease appears and progresses, the more targets become available for the development of novel therapies. Areas covered: Filgotinib is one of these promising new therapies; this article discusses the currently available data. We used an exhaustive search of the PubMed database to corroborate information regarding its chemical characteristics, and the studies evaluating clinical efficacy and safety. Expert opinion: Up to now, the phase-II study evaluating Filgotinib yielded very promising results in moderate to severe CD patients, with good clinical response, mucosal healing, while having few and moderate adverse effects, both in anti-TNF naïve and resistant patients. Phase-III studies are still ongoing and will help decide whether Filgotinib will be a worthwhile drug in the treatment of CD and the best way to use it.

Randomized Phase III Trial Comparing ABVD Plus Radiotherapy With the Stanford V Regimen in Patients With Stages I or II Locally Extensive, Bulky Mediastinal Hodgkin Lymphoma: A Subset Analysis of the North American Intergroup E2496 Trial.

PubMed

Advani, Ranjana H; Hong, Fangxin; Fisher, Richard I; Bartlett, Nancy L; Robinson, K Sue; Gascoyne, Randy D; Wagner, Henry; Stiff, Patrick J; Cheson, Bruce D; Stewart, Douglas A; Gordon, Leo I; Kahl, Brad S; Friedberg, Jonathan W; Blum, Kristie A; Habermann, Thomas M; Tuscano, Joseph M; Hoppe, Richard T; Horning, Sandra J

2015-06-10

The phase III North American Intergroup E2496 Trial (Combination Chemotherapy With or Without Radiation Therapy in Treating Patients With Hodgkin's Lymphoma) compared doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) with mechlorethamine, doxorubicin, vincristine, bleomycin, vinblastine, etoposide, and prednisone (Stanford V). We report results of a planned subgroup analysis in patients with stage I or II bulky mediastinal Hodgkin lymphoma (HL). Patients were randomly assigned to six to eight cycles of ABVD every 28 days or Stanford V once per week for 12 weeks. Two to 3 weeks after completion of chemotherapy, all patients received 36 Gy of modified involved field radiotherapy (IFRT) to the mediastinum, hila, and supraclavicular regions. Patients on the Stanford V arm received IFRT to additional sites ≥ 5 cm at diagnosis. Primary end points were failure-free survival (FFS) and overall survival (OS). Of 794 eligible patients, 264 had stage I or II bulky disease, 135 received ABVD, and 129 received Stanford V. Patient characteristics were matched. The overall response rate was 83% with ABVD and 88% with Stanford V. At a median follow-up of 6.5 years, the study excluded a difference of more than 21% in 5-year FFS and more than 16% in 5-year OS between ABVD and Stanford V (5-year FFS: 85% v 79%; HR, 0.68; 95% CI, 0.37 to 1.25; P = .22; 5-year OS: 96% v 92%; HR, 0.49; 95% CI, 0.16 to 1.47; P = .19). In-field relapses occurred in < 10% of the patients in each arm. For patients with stage I or II bulky mediastinal HL, no substantial statistically significant differences were detected between the two regimens, although power was limited. To the best of our knowledge, this is the first prospective trial reporting outcomes specific to this subgroup, and it sets a benchmark for comparison of ongoing and future studies. © 2015 by American Society of Clinical Oncology.

Alabama Coronary Artery Bypass Grafting Project

PubMed Central

Holman, William L.; Sansom, Monique; Kiefe, Catarina I.; Peterson, Eric D.; Hubbard, Steve G.; Delong, James F.; Allman, Richard M.

2004-01-01

Objective/Background: This report describes the first round of results for Phase II of the Alabama CABG Project, a regional quality improvement initiative. Methods: Charts submitted by all hospitals in Alabama performing CABG (ICD-9 codes 36.10–36.20) were reviewed by a Clinical Data Abstraction Center (CDAC) (preintervention 1999–2000; postintervention 2000–2001). Variables that described quality in Phase I were abstracted for Phase II and data describing the new variables of β-blocker use and lipid management were collected. Data samples collected onsite by participating hospitals were used for rapid cycle improvement in Phase II. Results: CDAC data (n = 1927 cases in 1999; n = 2001 cases in 2000) showed that improvements from Phase I in aspirin prescription, internal mammary artery use, and duration of intubation persisted in Phase II. During Phase II, use of β-blockers before, during, or after CABG increased from 65% to 76% of patients (P < 0.05). Appropriate lipid management, an aggregate variable, occurred in 91% of patients before and 91% after the educational intervention. However, there were improvements in 3 of 5 subcategories for lipid management (documenting a lipid disorder [52%–57%], initiating drug therapy [45%–53%], and dietary counseling [74%–91%]; P < 0.05). Conclusions: In Phase II, this statewide process-oriented quality improvement program added two new measures of quality. Achievements of quality improvement from Phase I persisted in Phase II, and improvements were seen in the new variables of lipid management and perioperative use of β-blockers. PMID:14685107

Electric Utility Phase I Acid Rain Compliance Strategies for the Clean Air Act Amendments of 1990

EIA Publications

1994-01-01

The Acid Rain Program is divided into two time periods; Phase I, from 1995 through 1999, and Phase II, starting in 2000. Phase I mostly affects power plants that are the largest sources of SO2 and NOx . Phase II affects virtually all electric power producers, including utilities and nonutilities. This report is a study of the effects of compliance with Phase I regulations on the costs and operations of electric utilities, but does not address any Phase II impacts.

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 - ...

Ion Conduction Path and Low-Temperature Form:. Argyrodite-Type Superionic Conductors

NASA Astrophysics Data System (ADS)

Onoda, M.; Wada, H.; Sato, A.; Ishii, M.

2007-01-01

The structures of the orthorhombic room-temperature phase of Cu8GeS6 (phase II) and the monoclinic low-temperature phase of Ag7TaS6 (phase II) have been successfully refined based on X-ray diffraction data from 12-fold twinned (Cu8GeS6 II) and 24-fold twinned (Ag7TaS6 II) crystals. Respectively among 6 major and 6 minor twin domains of Cu8GeS6 II, or among 12 major and 12 minor twin domains of Ag7TaS6 II, the argyrodite-type frameworks, GeS6 or TaS6, can be superposed to each other in principle, and only Cu-Cu or Ag-Ag network directions differ. At higher temperature, the crystals were considered to be 2-fold twinned crystals of superionic-conductor phase I with a space group F 43m. On cooling, each domain transforms into 6 domains of orthorhombic Cu8GeS6 II or 12 domains of monoclinic Ag7TaS6 II. Superposed projections along 6 directions of the structure of Cu8GeS6 II and along 12 directions of the structure of Ag7TaS6 II seem to show approximate expressions for Cu-ion and Ag-ion conduction paths in superionic-conductor phases, Cu8GeS6 I and Ag7TaS6I.

Weather information integration in transportation management center (TMC) operations.

DOT National Transportation Integrated Search

2011-01-02

This report presents the results of the third phase of an on-going FHWA study on weather integration in Transportation Management Center (TMC) operations. The report briefly describes the earlier phases of the integration study, summarizes the findin...

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.

KRAS and colorectal cancer: ethical and pragmatic issues in effecting real-time change in oncology clinical trials and practice.

PubMed

Blanke, Charles D; Goldberg, Richard M; Grothey, Axel; Mooney, Margaret; Roach, Nancy; Saltz, Leonard B; Welch, John J; Wood, William A; Meropol, Neal J

2011-01-01

Systemic therapy has led to a median survival time for patients with advanced colorectal cancer (CRC) almost fourfold longer than that expected with best supportive care, an outcome achieved through combining chemotherapeutic and targeted biologic agents. Although the latter can include anti-epidermal growth factor receptor antibodies, such as cetuximab and panitumumab, we now have strong evidence that patients whose tumors harbor mutated KRAS will not benefit from this class of agent. Acceptance of the reliability and importance of the KRAS data took several years to evolve, however, for a variety of reasons. The timeline from the presentation and publication of small, retrospective phase II studies to widespread acceptance of the KRAS predictive value and changes in behavior-specifically, modifications of ongoing national trials in advanced/metastatic CRC, changes in national guidelines and practice patterns, and adjustments to the labeled indications for the monoclonal antibodies-was lengthy. In this commentary, we discuss whether or not the process of data disclosure regarding KRAS status and treatment of advanced CRC patients was effective in permitting timely decisions regarding ongoing publicly funded clinical trials and whether or not such decisions were rational and ethical. The overall goals are to highlight lessons learned regarding early disclosure of clinical trial results, as well as vetting and adoption of new scientific data, and to propose modifications for handling similar situations in the future.

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.

ASR-9 processor augmentation card (9-PAC) phase II scan-scan correlator algorithms

DOT National Transportation Integrated Search

2001-04-26

The report documents the scan-scan correlator (tracker) algorithm developed for Phase II of the ASR-9 Processor Augmentation Card (9-PAC) project. The improved correlation and tracking algorithms in 9-PAC Phase II decrease the incidence of false-alar...

Pharmacodynamics, pharmacokinetics and clinical efficacy of neratinib in HER2-positive breast cancer and breast cancer with HER2 mutations.

PubMed

Kourie, Hampig Raphael; Chaix, Marie; Gombos, Andrea; Aftimos, Phillippe; Awada, Ahmad

2016-08-01

Despite the availability of several potent HER2-directed targeted agents, primary and acquired resistance continues to influence patient outcomes in HER2-positive breast cancer. Neratinib is an irreversible pan-HER tyrosine kinase inhibitor in late-phase clinical development. This review article focuses on neratinib in the treatment of HER2-positive breast cancer - early and metastatic stage - and HER2-mutant breast cancer, with particular emphasis on the pharmacokinetics and pharmacodynamics of the drug. The phase III ExteNET trial shows that neratinib improves 2-year invasive disease-free survival after trastuzumab-based adjuvant therapy in early-stage HER2-positive breast cancer, and in particular HER2+/HR+ tumors. Survival data are awaited. The investigational role of neratinib in high-risk patients or conversely in de-escalation dual regimens with other anti-HER2 therapies and without chemotherapy are of interest. Phase II trials show that neratinib has efficacy, either as monotherapy or in combination with other chemotherapeutic or endocrine agents, in patients with HER2-positive metastatic breast cancer and in tumors harboring HER2 mutations. The role of neratinib in therapeutic algorithms of HER2-positive patients, as well as delaying CNS events, awaits the results of ongoing trials such as NALA. Diarrhea, the main toxicity of neratinib, can be effectively managed with early loperamide prophylaxis.

Atezolizumab: A novel PD-L1 inhibitor in cancer therapy with a focus in bladder and non-small cell lung cancers.

PubMed

Krishnamurthy, A; Jimeno, A

2017-04-01

In recent years, immunotherapy has come to the forefront as a major development in cancer treatment. Evasion of the immune system by tumor cells has been identified as one of the hallmarks of cancer and multiple therapies have been developed to counter this process. Programmed cell death 1 ligand 1 (PD-L1), a ligand to programmed cell death protein 1 (PD-1), is expressed by many cancer cells and the binding of PD-L1 to PD-1 results in the suppression of T-cell-mediated immune response against cancer cells. Atezolizumab is a monoclonal antibody that binds to PD-L1 and blocks its interaction with PD-1, thereby enhancing T-cell activity against tumor cells. Atezolizumab has been shown to be well tolerated with no dose-limiting toxicities in phase I trials. Atezolizumab was approved by the U.S. Food and Drug Administration in 2016 for the treatment of platinum-resistant metastatic non-small cell lung cancer (NSCLC) and urothelial cancer based on phase II and preliminary phase III studies that have shown significant improvement in objective response rate and median overall survival. There are 117 ongoing clinical trials of atezolizumab currently. Given its efficacy in NSCLC and urothelial carcinoma, atezolizumab holds much potential in the future of cancer therapeutics. Copyright 2017 Clarivate Analytics.

Accidents at Nuclear Power Plants and Cancer Risk

MedlinePlus

... of the Chernobyl accident, survivors of the atomic bomb explosions in Japan during World War II, and ... about the health effects from the 1945 atomic bomb exposures in that country. This ongoing project is ...

Mechanisms of blood pressure alterations in response to the Valsalva maneuver in postural tachycardia syndrome

NASA Technical Reports Server (NTRS)

Sandroni, P.; Novak, V.; Opfer-Gehrking, T. L.; Huck, C. A.; Low, P. A.

2000-01-01

The postural tachycardia syndrome (POTS) is characterized clinically by orthostatic lightheadedness and tachycardia. When these patients perform a Valsalva maneuver, there is an excessive blood pressure increment after cessation of the maneuver (phase IV) that is sometimes associated with headaches. It is not known whether excessive phase IV is due to excessive peripheral vascular tone (an alpha-adrenergic mechanism) or is a manifestation of increased beta-adrenergic tone (hyperadrenergic state). The authors undertook a pharmacologic study evaluating the effect of intravenous phentolamine (alpha-adrenergic antagonist) and propranolol (beta-adrenergic antagonist) on the different phases of the Valsalva maneuver in a group of patients with POTS and age-matched normal control subjects. Patients with POTS had mean phases, when compared with controls, that were characterized by more negative II_E (p = 0.07), smaller II_L (p = 0.04), and significantly larger phase IV (p = 0.001). The effect of phentolamine was qualitatively and quantitatively different in POTS when compared with controls. Ten mg phentolamine in controls resulted in a significant accentuation of phase II_E (p = 0.001), attenuation of phase II_L (p = 0.002), and increase of phase IV (57.6 vs 30.7 mm Hg; p = 0.025). These changes resembled those of patients with POTS at baseline. In patients with POTS, the phase II abnormalities, already present, were further accentuated (p <0.001), and phase IV became smaller (50.6 vs 73.8 mm Hg; p = 0.09). Propranolol had no significant effect on phases II_E and II_L, but significantly reduced phase IV in both controls (p <0.05) and in patients with POTS (p <0.001) and improved the headache symptoms, when present, during and after phase IV. The authors conclude that phase IV is mainly under beta-adrenergic regulation and that the exaggerated phase IV in POTS is a result of a hyperadrenergic state.

TNX GeoSiphon Cell (TGSC-1) Phase II Single Cell Deployment/Demonstration Final Report

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

Phifer, M.A.

1999-04-15

This Phase II final report documents the Phase II testing conducted from June 18, 1998 through November 13, 1998, and it focuses on the application of the siphon technology as a sub-component of the overall GeoSiphon Cell technology. [Q-TPL-T-00004

40 CFR 72.44 - Phase II repowering extensions.

Code of Federal Regulations, 2012 CFR

2012-07-01

... (CONTINUED) PERMITS REGULATION Acid Rain Compliance Plan and Compliance Options § 72.44 Phase II repowering... the requirements of paragraph (a)(1)(i) of this section may include in the unit's Phase II Acid Rain... authority shall issue the Acid Rain portion of the operating permit including: (A) The approved repowering...

40 CFR 72.44 - Phase II repowering extensions.

Code of Federal Regulations, 2011 CFR

2011-07-01

... (CONTINUED) PERMITS REGULATION Acid Rain Compliance Plan and Compliance Options § 72.44 Phase II repowering... the requirements of paragraph (a)(1)(i) of this section may include in the unit's Phase II Acid Rain... authority shall issue the Acid Rain portion of the operating permit including: (A) The approved repowering...

40 CFR 72.44 - Phase II repowering extensions.

Code of Federal Regulations, 2013 CFR

2013-07-01

... (CONTINUED) PERMITS REGULATION Acid Rain Compliance Plan and Compliance Options § 72.44 Phase II repowering... the requirements of paragraph (a)(1)(i) of this section may include in the unit's Phase II Acid Rain... authority shall issue the Acid Rain portion of the operating permit including: (A) The approved repowering...

40 CFR 72.44 - Phase II repowering extensions.

Code of Federal Regulations, 2010 CFR

2010-07-01

... (CONTINUED) PERMITS REGULATION Acid Rain Compliance Plan and Compliance Options § 72.44 Phase II repowering... the requirements of paragraph (a)(1)(i) of this section may include in the unit's Phase II Acid Rain... authority shall issue the Acid Rain portion of the operating permit including: (A) The approved repowering...

40 CFR 72.44 - Phase II repowering extensions.

Code of Federal Regulations, 2014 CFR

2014-07-01

... (CONTINUED) PERMITS REGULATION Acid Rain Compliance Plan and Compliance Options § 72.44 Phase II repowering... the requirements of paragraph (a)(1)(i) of this section may include in the unit's Phase II Acid Rain... authority shall issue the Acid Rain portion of the operating permit including: (A) The approved repowering...

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

PubMed

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

2018-05-01

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

77 FR 71798 - Proposed Data Collections Submitted for Public Comment and Recommendations

Federal Register 2010, 2011, 2012, 2013, 2014

2012-12-04

... ongoing manner, most of the more than 4,500 hospitals now reporting to the CDC's current HAI surveillance... of nine acute care hospitals in one U.S. city. This pilot phase was followed in 2010 by a phase 2..., Maryland, Minnesota, New Mexico, New York, Oregon, and Tennessee). Experience gained in the phase 1 and...

The Lunar Phases Project: A Mental Model-Based Observational Project for Undergraduate Nonscience Majors

ERIC Educational Resources Information Center

Meyer, Angela Osterman; Mon, Manuel J.; Hibbard, Susan T.

2011-01-01

We present our Lunar Phases Project, an ongoing effort utilizing students' actual observations within a mental model building framework to improve student understanding of the causes and process of the lunar phases. We implement this project with a sample of undergraduate, nonscience major students enrolled in a midsized public university located…

Self-management toolkit and delivery strategy for end-of-life pain: the mixed-methods feasibility study.

PubMed

Bennett, Michael I; Mulvey, Matthew R; Campling, Natasha; Latter, Sue; Richardson, Alison; Bekker, Hilary; Blenkinsopp, Alison; Carder, Paul; Closs, Jose; Farrin, Amanda; Flemming, Kate; Gallagher, Jean; Meads, David; Morley, Stephen; O'Dwyer, John; Wright-Hughes, Alexandra; Hartley, Suzanne

2017-12-01

Pain affects most people approaching the end of life and can be severe for some. Opioid analgesia is effective, but evidence is needed about how best to support patients in managing these medicines. To develop a self-management support toolkit (SMST) and delivery strategy and to test the feasibility of evaluating this intervention in a future definitive trial. Phase I - evidence synthesis and qualitative interviews with patients and carers. Phase II - qualitative semistructured focus groups and interviews with patients, carers and specialist palliative care health professionals. Phase III - multicentre mixed-methods single-arm pre-post observational feasibility study. Phase I - six patients and carers. Phase II - 15 patients, four carers and 19 professionals. Phase III - 19 patients recruited to intervention that experienced pain, living at home and were treated with strong opioid analgesia. Process evaluation interviews with 13 patients, seven carers and 11 study nurses. Self-Management of Analgesia and Related Treatments at the end of life (SMART) intervention comprising a SMST and a four-step educational delivery approach by clinical nurse specialists in palliative care over 6 weeks. Recruitment rate, treatment fidelity, treatment acceptability, patient-reported outcomes (such as scores on the Brief Pain Inventory, Self-Efficacy for Managing Chronic Disease Scale, Edmonton Symptom Assessment Scale, EuroQol-5 Dimensions, Satisfaction with Information about Medicines Scale, and feasibility of collecting data on health-care resource use for economic evaluation). Phase I - key themes on supported self-management were identified from evidence synthesis and qualitative interviews. Phase II - the SMST was developed and refined. The delivery approach was nested within a nurse-patient consultation. Phase III - intervention was delivered to 17 (89%) patients, follow-up data at 6 weeks were available on 15 patients. Overall, the intervention was viewed as acceptable and valued. Descriptive analysis of patient-reported outcomes suggested that interference from pain and self-efficacy were likely to be candidates for primary outcomes in a future trial. No adverse events related to the intervention were reported. The health economic analysis suggested that SMART could be cost-effective. We identified key limitations and considerations for a future trial: improve recruitment through widening eligibility criteria, refine the SMST resources content, enhance fidelity of intervention delivery, secure research nurse support at recruiting sites, refine trial procedures (including withdrawal process and data collection frequency), and consider a cluster randomised design with nurse as cluster unit. (1) The recruitment rate was lower than anticipated. (2) The content of the intervention was focused on strong opioids only. (3) The fidelity of intervention delivery was limited by the need for ongoing training and support. (4) Recruitment sites where clinical research nurse support was not secured had lower recruitment rates. (5) The process for recording withdrawal was not sufficiently detailed. (6) The number of follow-up visits was considered burdensome for some participants. (7) The feasibility trial did not have a control arm or assess randomisation processes. A future randomised controlled trial is feasible and acceptable. This study is registered as PROSPERO CRD42014013572; Current Controlled Trials ISRCTN35327119; and National Institute for Health Research (NIHR) Portfolio registration 162114. The NIHR Health Technology Assessment programme.

Comparison of V-4 and V-5 Exercise/Oxygen Prebreathe Protocols to Support Extravehicular Activity in Microgravity

NASA Technical Reports Server (NTRS)

Pollock, N. W.; Natoli, M. J.; Vann, R. D.; Gernhardt, M. L.; Conkin, Johnny

2007-01-01

The Prebreathe Reduction Program (PRP) used exercise during oxygen prebreathe to reduce necessary prebreathe time prior to depressurizing to work in a 4.3 psi suit during extravehicular activity (EVA). Initial testing produced a two-hour protocol incorporating ergometry exercise and a 30 min cycle of depress/repress to 10.2 psi where subjects breathed 26.5% oxygen/balance nitrogen (Phase II - 10 min at 75% peak oxygen consumption [VO2 peak] followed by 40 min intermittent light exercise [ILE] [approx. 5.8 mL-per kilogram- per minute], then 50 min of rest). The Phase II protocol (0/45 DCS) was approved for operations and has been used on 40 EVAs, providing significant time savings compared to the standard 4 h resting oxygen prebreathe. The Phase V effort focused on performing all light in-suit exercise. Two oxygen prebreathe protocols were tested sequentially: V-4) 160 min prebreathe with 150 min of continuous ILE. The entire protocol was completed at 14.7 psi. All exercise involved upper body effort. Exercise continued until decompression. V-5) 160 min prebreathe with 140 min of ILE - first 40 min at 14.7 psi, then 30 min at 10.2 psi (breathing 26.5% oxygen) after a 20 min depress, simulating a suit donning period. Subjects were then repressed to 14.7 psi and performed another 50 min of lower body ILE, followed by 50 min rest before decompression. The V-4 protocol was rejected with 3 DCS/6 person-exposures. Initial V-5 testing has produced 0 DCS/11 person-exposures (ongoing trials). The difference in DCS rate was significant (Fisher Exact p=0.029). The observations of DCS were significantly lower in early V-5 trials than in V-4 trials. Additional studies are required to evaluate the relative contribution of the variables in exercise distribution, the 10.2 psi depress/repress component, pre-decompression rest, or possible variation in total oxygen consumption.

Phase II multi-institutional clinical trial on a new mixed beam RT scheme of IMRT on pelvis combined with a carbon ion boost for high-risk prostate cancer patients.

PubMed

Marvaso, Giulia; Jereczek-Fossa, Barbara A; Vischioni, Barbara; Ciardo, Delia; Giandini, Tommaso; Hasegawa, Azusa; Cattani, Federica; Carrara, Mauro; Ciocca, Mario; Bedini, Nice; Villa, Sergio; Morlino, Sara; Russo, Stefania; Zerini, Dario; Colangione, Sarah Pia; Panaino, Costanza Maria Vittoria; Fodor, Cristiana; Santoro, Luigi; Pignoli, Emanuele; Valvo, Francesca; Valdagni, Riccardo; De Cobelli, Ottavio; Orecchia, Roberto

2017-05-12

Definition of the optimal treatment schedule for high-risk prostate cancer is under debate. A combination of photon intensity modulated radiotherapy (IMRT) on pelvis with a carbon ion boost might be the optimal treatment scheme to escalate the dose on prostate and deliver curative dose with respect to normal tissue and quality of dose distributions. In fact, carbon ion beams offer the advantage to deliver hypofractionated radiotherapy (RT) using a significantly smaller number of fractions compared to conventional RT without increasing risks of late effects. This study is a prospective phase II clinical trial exploring safety and feasibility of a mixed beam scheme of carbon ion prostate boost followed by photon IMRT on pelvis. The study is designed to enroll 65 patients with localized high-risk prostate cancer at 3 different oncologic hospitals: Istituto Europeo di Oncologia, Fondazione IRCCS Istituto Nazionale dei Tumori, and Centro Nazionale di Adroterapia Oncologica. The primary endpoint is the evaluation of safety and feasibility with acute toxicity scored up to 1 month after the end of RT. Secondary endpoints are treatment early (3 months after the end of RT) and long-term tolerability, quality of life, and efficacy. The study is not yet recruiting; in silico studies are ongoing and we expect to start recruitment by 2017. The present clinical trial aims at improving the current treatment for high-risk prostate cancer, evaluating safety and feasibility of a new RT mixed-beam scheme including photons and carbon ions. Encouraging results are coming from carbon ion facilities worldwide on the treatment of different tumors including prostate cancers. Carbon ions combine physical properties allowing for high dose conformity and advantageous radiobiological characteristics. The proposed mixed beam treatment has the advantage to combine a photon high conformity standard of care IMRT phase with a hypofractionated carbon ion RT boost delivered in a short overall treatment time.

Phase I Pharmacokinetic and Pharmacodynamic Study of the Oral, Small-Molecule Mitogen-Activated Protein Kinase Kinase 1/2 Inhibitor AZD6244 (ARRY-142886) in Patients With Advanced Cancers

PubMed Central

Adjei, Alex A.; Cohen, Roger B.; Franklin, Wilbur; Morris, Clive; Wilson, David; Molina, Julian R.; Hanson, Lorelei J.; Gore, Lia; Chow, Laura; Leong, Stephen; Maloney, Lara; Gordon, Gilad; Simmons, Heidi; Marlow, Allison; Litwiler, Kevin; Brown, Suzy; Poch, Gregory; Kane, Katie; Haney, Jerry; Eckhardt, S. Gail

2009-01-01

Purpose To assess the tolerability, pharmacokinetics (PKs), and pharmacodynamics (PDs) of the mitogen-activated protein kinase kinase (MEK) 1/2 inhibitor AZD6244 (ARRY-142886) in patients with advanced cancer. Patients and Methods In part A, patients received escalating doses to determine the maximum-tolerated dose (MTD). In both parts, blood samples were collected to assess PK and PD parameters. In part B, patients were stratified by cancer type (melanoma v other) and randomly assigned to receive the MTD or 50% MTD. Biopsies were collected to determine inhibition of ERK phosphorylation, Ki-67 expression, and BRAF, KRAS, and NRAS mutations. Results Fifty-seven patients were enrolled. MTD in part A was 200 mg bid, but this dose was discontinued in part B because of toxicity. The 50% MTD (100 mg bid) was well tolerated. Rash was the most frequent and dose-limiting toxicity. Most other adverse events were grade 1 or 2. The PKs were less than dose proportional, with a median half-life of approximately 8 hours and inhibition of ERK phosphorylation in peripheral-blood mononuclear cells at all dose levels. Paired tumor biopsies demonstrated reduced ERK phosphorylation (geometric mean, 79%). Five of 20 patients demonstrated ≥ 50% inhibition of Ki-67 expression, and RAF or RAS mutations were detected in 10 of 26 assessable tumor samples. Nine patients had stable disease (SD) for ≥ 5 months, including two patients with SD for 19 (thyroid cancer) and 22 (uveal melanoma plus renal cancer) 28-day cycles. Conclusion AZD6244 was well tolerated with target inhibition demonstrated at the recommended phase II dose. PK analyses supported twice-daily dosing. Prolonged SD was seen in a variety of advanced cancers. Phase II studies are ongoing. PMID:18390968

FIR: Efficacy, Safety, and Biomarker Analysis of a Phase II Open-Label Study of Atezolizumab in PD-L1-Selected Patients with Non-Small-Cell Lung Cancer.

PubMed

Spigel, David R; Chaft, Jamie E; Gettinger, Scott; Chao, Bo H; Dirix, Luc; Schmid, Peter; Chow, Laura Q M; Hicks, Rodney J; Leon, Larry; Fredrickson, Jill; Kowanetz, Marcin; Sandler, Alan; Funke, Roel; Rizvi, Naiyer A

2018-05-15

The FIR phase II study (NCT01846416) evaluated the efficacy and safety of anti-programmed death-ligand 1 (PD-L1) atezolizumab in advanced non-small-cell lung cancer (NSCLC) selected by tumor cell (TC) or tumor-infiltrating immune cell (IC) PD-L1 expression. Patients with PD-L1 TC2/3 (PD-L1 staining on ≥5% of TC) or IC2/3 tumors (PD-L1 staining on ≥5% of IC; determined by SP142 PD-L1 immunohistochemistry assay) with paired fresh and archival histology samples were recruited into Cohort 1 (chemotherapy-naïve/>6 months between adjuvant chemotherapy and recurrence), Cohort 2 (≥ second-line without brain metastases), or Cohort 3 (≥ second-line with treated brain metastases). Patients received 1200 mg atezolizumab, Day 1 (21-day cycles). Primary endpoint: investigator-assessed modified Response Evaluation Criteria in Solid Tumors (mRECIST), objective response rate (ORR; RECIST v1.1). Secondary endpoints: overall survival, progression-free survival, duration of response, safety. Patients (n=138) were enrolled (137 evaluable for response: Cohort 1, n=31; Cohort 2, n=93; Cohort 3, n=13). Investigator-assessed ORR was 32%, 21%, and 23% for Cohorts 1, 2, and 3, respectively. Treatment-related adverse events (TRAEs) were reported in 81%, 67%, and 69% of patients, respectively, including grade 3-4 TRAEs in 16%, 19%, and 15%. Moreover, 88.6% (n=86/97) paired baseline tumor samples had <5% change in TC/IC PD-L1 expression over time. Atezolizumab monotherapy showed clinical activity in patients with NSCLC, including those with brain metastases; safety was consistent with previous trials. Atezolizumab has completed phase III monotherapy studies in second-line; front-line trials are ongoing, confirming these favorable results. Copyright © 2018. Published by Elsevier Inc.

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.

Benefits and Sustainability of a Learning Collaborative for Implementation of Treat to Target in Rheumatoid Arthritis: Results of the TRACTION Trial Phase II.

PubMed

Solomon, Daniel H; Lu, Bing; Yu, Zhi; Corrigan, Cassandra; Harrold, Leslie R; Smolen, Josef S; Fraenkel, Liana; Katz, Jeffrey N; Losina, Elena

2018-01-05

We conducted a two-phase randomized controlled trial of a Learning Collaborative (LC) to facilitate implementation of treat to target (TTT) to manage rheumatoid arthritis (RA). We found substantial improvement in implementation of TTT in Phase I. Herein, we report on a second 9 months (Phase II) where we examined maintenance of response in Phase I and predictors of greater improvement in TTT adherence. We recruited 11 rheumatology sites and randomized them to either receive the LC during Phase I or to a wait-list control group that received the LC intervention during Phase II. The outcome was change in TTT implementation score (0 to 100, 100 is best) from pre- to post-intervention. TTT implementation score is defined as a percent of components documented in visit notes. Analyses examined: 1) the extent that the Phase I intervention teams sustained improvement in TTT; and, 2) predictors of TTT improvement. The analysis included 636 RA patients. At baseline, mean TTT implementation score was 11% in Phase I intervention sites and 13% in Phase II sites. After the intervention, TTT implementation score improved to 57% in the Phase I intervention sites and to 58% in the Phase II sites. Intervention sites from Phase I sustained the improvement during the Phase II (52%). Predictors of greater TTT improvement included only having rheumatologist providers at the site, academic affiliation of the site, fewer providers per site, and the rheumatologist provider being a trainee. Improvement in TTT remained relatively stable over a post-intervention period. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

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

Processing closely spaced lesions during Nucleotide Excision Repair triggers mutagenesis in E. coli

PubMed Central

Isogawa, Asako; Fujii, Shingo

2017-01-01

It is generally assumed that most point mutations are fixed when damage containing template DNA undergoes replication, either right at the fork or behind the fork during gap filling. Here we provide genetic evidence for a pathway, dependent on Nucleotide Excision Repair, that induces mutations when processing closely spaced lesions. This pathway, referred to as Nucleotide Excision Repair-induced Mutagenesis (NERiM), exhibits several characteristics distinct from mutations that occur within the course of replication: i) following UV irradiation, NER-induced mutations are fixed much more rapidly (t ½ ≈ 30 min) than replication dependent mutations (t ½ ≈ 80–100 min) ii) NERiM specifically requires DNA Pol IV in addition to Pol V iii) NERiM exhibits a two-hit dose-response curve that suggests processing of closely spaced lesions. A mathematical model let us define the geometry (infer the structure) of the toxic intermediate as being formed when NER incises a lesion that resides in close proximity of another lesion in the complementary strand. This critical NER intermediate requires Pol IV / Pol II for repair, it is either lethal if left unrepaired or mutation-prone when repaired. Finally, NERiM is found to operate in stationary phase cells providing an intriguing possibility for ongoing evolution in the absence of replication. PMID:28686598

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

PubMed

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

2011-09-23

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

MECHANISM AND KINETICS OF THE FORMATION OF NOX AND OTHER COMBUSTION POLLUTANTS. PHASE II. MODIFIED COMBUSTION

EPA Science Inventory

The report gives Phase II results of a combined experimental/theoretical study to define the mechanisms and kinetics of the formation of NOx and other combustion pollutants. Two experimental devices were used in Phase II. A special flat-flame burner with a controlled-temperature ...

76 FR 3624 - Milford Wind Corridor Phase II, LLC; Supplemental Notice That Initial Market-Based Rate Filing...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-01-20

... DEPARTMENT OF ENERGY Federal Energy Regulatory Commission [Docket No. ER11-2657-000] Milford Wind Corridor Phase II, LLC; Supplemental Notice That Initial Market-Based Rate Filing Includes Request for... proceeding Milford Wind Corridor Phase II, LLC's application for market-based rate authority, with an...

40 CFR 72.73 - State issuance of Phase II permits.

Code of Federal Regulations, 2010 CFR

2010-07-01

... (CONTINUED) PERMITS REGULATION Acid Rain Phase II Implementation § 72.73 State issuance of Phase II permits... permit program under part 70 of this chapter and that has a State Acid Rain program accepted by the Administrator under § 72.71 shall be responsible for administering and enforcing Acid Rain permits effective in...

40 CFR 72.73 - State issuance of Phase II permits.

Code of Federal Regulations, 2014 CFR

2014-07-01

... (CONTINUED) PERMITS REGULATION Acid Rain Phase II Implementation § 72.73 State issuance of Phase II permits... permit program under part 70 of this chapter and that has a State Acid Rain program accepted by the Administrator under § 72.71 shall be responsible for administering and enforcing Acid Rain permits effective in...

40 CFR 72.73 - State issuance of Phase II permits.

Code of Federal Regulations, 2012 CFR

2012-07-01

... (CONTINUED) PERMITS REGULATION Acid Rain Phase II Implementation § 72.73 State issuance of Phase II permits... permit program under part 70 of this chapter and that has a State Acid Rain program accepted by the Administrator under § 72.71 shall be responsible for administering and enforcing Acid Rain permits effective in...

40 CFR 72.73 - State issuance of Phase II permits.

Code of Federal Regulations, 2013 CFR

2013-07-01

... (CONTINUED) PERMITS REGULATION Acid Rain Phase II Implementation § 72.73 State issuance of Phase II permits... permit program under part 70 of this chapter and that has a State Acid Rain program accepted by the Administrator under § 72.71 shall be responsible for administering and enforcing Acid Rain permits effective in...

40 CFR 72.74 - Federal issuance of Phase II permits.

Code of Federal Regulations, 2010 CFR

2010-07-01

... PROGRAMS (CONTINUED) PERMITS REGULATION Acid Rain Phase II Implementation § 72.74 Federal issuance of Phase II permits. (a)(1) The Administrator will be responsible for administering and enforcing Acid Rain... and enforcing Acid Rain permits for such sources under § 72.73(a). (2) After and to the extent the...

40 CFR 72.74 - Federal issuance of Phase II permits.

Code of Federal Regulations, 2014 CFR

2014-07-01

... PROGRAMS (CONTINUED) PERMITS REGULATION Acid Rain Phase II Implementation § 72.74 Federal issuance of Phase II permits. (a)(1) The Administrator will be responsible for administering and enforcing Acid Rain... and enforcing Acid Rain permits for such sources under § 72.73(a). (2) After and to the extent the...

40 CFR 72.74 - Federal issuance of Phase II permits.

Code of Federal Regulations, 2012 CFR

2012-07-01

... PROGRAMS (CONTINUED) PERMITS REGULATION Acid Rain Phase II Implementation § 72.74 Federal issuance of Phase II permits. (a)(1) The Administrator will be responsible for administering and enforcing Acid Rain... and enforcing Acid Rain permits for such sources under § 72.73(a). (2) After and to the extent the...

40 CFR 72.74 - Federal issuance of Phase II permits.

Code of Federal Regulations, 2013 CFR

2013-07-01

... PROGRAMS (CONTINUED) PERMITS REGULATION Acid Rain Phase II Implementation § 72.74 Federal issuance of Phase II permits. (a)(1) The Administrator will be responsible for administering and enforcing Acid Rain... and enforcing Acid Rain permits for such sources under § 72.73(a). (2) After and to the extent the...

40 CFR 72.73 - State issuance of Phase II permits.

Code of Federal Regulations, 2011 CFR

2011-07-01

... (CONTINUED) PERMITS REGULATION Acid Rain Phase II Implementation § 72.73 State issuance of Phase II permits... permit program under part 70 of this chapter and that has a State Acid Rain program accepted by the Administrator under § 72.71 shall be responsible for administering and enforcing Acid Rain permits effective in...

40 CFR 72.74 - Federal issuance of Phase II permits.

Code of Federal Regulations, 2011 CFR

2011-07-01

... PROGRAMS (CONTINUED) PERMITS REGULATION Acid Rain Phase II Implementation § 72.74 Federal issuance of Phase II permits. (a)(1) The Administrator will be responsible for administering and enforcing Acid Rain... and enforcing Acid Rain permits for such sources under § 72.73(a). (2) After and to the extent the...

Doping-induced disappearance of ice II from water's phase diagram

NASA Astrophysics Data System (ADS)

Shephard, Jacob J.; Slater, Ben; Harvey, Peter; Hart, Martin; Bull, Craig L.; Bramwell, Steven T.; Salzmann, Christoph G.

2018-06-01

Water and the many phases of ice display a plethora of complex physical properties and phase relationships1-4 that are of paramount importance in a range of settings including processes in Earth's hydrosphere, the geology of icy moons, industry and even the evolution of life. Well-known examples include the unusual behaviour of supercooled water2, the emergent ferroelectric ordering in ice films4 and the fact that the `ordinary' ice Ih floats on water. We report the intriguing observation that ice II, one of the high-pressure phases of ice, disappears in a selective fashion from water's phase diagram following the addition of small amounts of ammonium fluoride. This finding exposes the strict topologically constrained nature of the ice II hydrogen-bond network, which is not found for the competing phases. In analogy to the behaviour of frustrated magnets5, the presence of the exceptional ice II is argued to have a wider impact on water's phase diagram, potentially explaining its general tendency to display anomalous behaviour. Furthermore, the impurity-induced disappearance of ice II raises the prospect that specific dopants may not only be able to suppress certain phases but also induce the formation of new phases of ice in future studies.

Selection of a discriminant and biorelevant in vitro dissolution test for the development of fenofibrate self-emulsifying lipid-based formulations.

PubMed

Pestieau, Aude; Krier, Fabrice; Brouwers, Adeline; Streel, Bruno; Evrard, Brigitte

2016-09-20

Fenofibrate, a BCS class II compound, has a low bioavailability especially when taken orally on an empty stomach. The challenge to find a new formulation for providing bioavailability, independent of food, is still ongoing. If the development of a suitable oral delivery formulation of BCS class II compounds is a frequent and great challenge to formulation scientists, the in vitro evaluation of these new formulations is also a great challenge. The purpose of this study was therefore to select an in vitro dissolution test that would be useful and as biorelevant as possible for the development of fenofibrate self-emulsifying lipid-based formulations. In this context, three different fenofibrate formulations, for which in vivo data are available in the literature, were tested using different dissolution tests until we found the one that was the most suitable. As part of this approach, we started with the simplest in vitro dissolution tests and progressed to tests that were increasingly more complex. The first tests were different single phase dissolution tests: a test under sink conditions based on the USP monograph, and different tests under non-sink conditions in non-biorelevant and biorelevant media. Given the inconclusive results obtained with these tests, biphasic dissolution systems were then tested: one with USP apparatus type II alone and another which combined USP apparatus types II and IV. This last combined test seemed the most suitable in vitro dissolution test for the development of the future fenofibrate lipid-based formulations we intend to develop in our own laboratory. Copyright © 2016 Elsevier B.V. All rights reserved.

Resolving Fe-rich Neutral ISM in a Massive Quiescent Galaxy at z 0.4

NASA Astrophysics Data System (ADS)

Zahedy, Fakhri

2016-10-01

Roughly 40% of elliptical galaxies are found to contain cool gas but exhibit no on-going star formation, indicating that some feedback mechanisms are at work. While AGN feedback is commonly thought to be responsible for quenching star formation in massive halos, recent work has reiterated the importance of feedback from old stellar populations, including Type Ia supernovae (SNe Ia). In Zahedy et al. (2016), we reported detections of ultra-strong MgII absorption (>3.6 Ang) at 1-2 effective radii of a massive quiescent lensing galaxy at z=0.408. Strong MgII, FeII, MgI, and CaII absorption are found at the lens redshift along two lensed QSO sightlines separated by 8 kpc. The absorbers are resolved into 15 components with line-of-sight velocity spread of 600 km/s. The large observed ionic column densities, N>1e14 cm^-2 suggest large neutral hydrogen column densities N(HI)>1e18 cm^-2 and a significant neutral gas fraction. The most striking feature is the uniformly large Fe/Mg ratio across the full 600 km/s velocity range, suggesting a large contribution in chemical enrichment from SNe Ia (>20%). Here we propose QSO absorption-line spectroscopy of this unique system using STIS and the G140L grating with the slit oriented along the two lensed QSOs. The goal is to determine N(HI) from observations of the full Lyman absorption series and gas-phase metallicity of the interstellar medium at two locations separated by 8 kpc in an elliptical galaxy beyond the local universe. With a modest investment of HST time, we will be able to examine the extent SNe Ia-driven feedback in a distant quiescent galaxy using this unique double-lens system.

Assessment of Operational Automated Guideway Systems - Airtrans (Phase II)

DOT National Transportation Integrated Search

1980-01-01

This study, Phase II, completes the assessment of AIRTRANS, the automated guideway system located at the Dallas-Fort Worth Airport. The Phase I assessment report: "Assessment of Operational Automated Guideway Systems--AIRTRANS (Phase I)" (PB-261 339)...

Attendance at specialist hepatitis clinics and initiation of antiviral treatment among persons chronically infected with hepatitis C: examining the early impact of Scotland's Hepatitis C Action Plan.

PubMed

McDonald, S A; Hutchinson, S J; Innes, H A; Allen, S; Bramley, P; Bhattacharyya, D; Carman, W; Dillon, J F; Fox, R; Fraser, A; Goldberg, D J; Kennedy, N; Mills, P R; Morris, J; Stanley, A J; Wilks, D; Hayes, P C

2014-05-01

Primary goals of the Hepatitis C Action Plan for Scotland Phase II (May 2008-March 2011) were to increase, among persons chronically infected with the hepatitis C (HCV) virus, attendance at specialist outpatient clinics and initiation on antiviral therapy. We evaluated progress towards these goals by comparing the odds, across time, of (a) first clinic attendance within 12 months of HCV diagnosis (n = 9747) and (b) initiation on antiviral treatment within 12 months of first attendance (n = 5736). Record linkage between the national HCV diagnosis (1996-2009) and HCV clinical (1996-2010) databases and logistic regression analyses were conducted for both outcomes. For outcome (a), 32% and 45% in the respective pre-Phase II (before 1 May 2008) and Phase II periods attended a specialist clinic within 12 months of diagnosis; the odds of attendance within 12 months increased over time (OR = 1.05 per year, 95% CI: 1.04-1.07), but was not significantly greater for persons diagnosed with HCV in the Phase II era, compared with the pre-Phase II era (OR = 1.1, 95% CI: 0.9-1.3), after adjustment for temporal trend. For outcome (b), 13% and 28% were initiated on treatment within 12 months of their first clinic attendance in the pre-Phase II and Phase II periods, respectively. Higher odds of treatment initiation were associated with first clinic attendance in the Phase II (OR = 1.9, 95% CI: 1.5-2.4), compared with the pre-Phase II era. Results were consistent with a positive impact of the Hepatitis C Action Plan on the treatment of chronically infected individuals, but further monitoring is required to confirm a sustained effect. © 2013 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.

Development of advanced blanket performance under irradiation and system integration through JUPITER-II project

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

Abe, Katsunori; Kohyama, Akira; Tanaka, Satoru

This report describes an outline of the activities of the JUPITER-II collaboration (japan-USA program of Irradiation/Integration test for Fusion Research-II), Which has bee carried out through six years (2001-2006) under Phase 4 of the collabroation implemented by Amendment 4 of Annex 1 to the DOE (United States Department of Energy)-MEXT (Ministry of Education ,Culture,Sports,Science and Technology) Cooperation. This program followed the RTNS-II Program (Phase1:1982-4986), the FFTF/MOTA Program (Phase2:1987-1994) and the JUPITER Program (Phase 3: 1995-2000) [1].

Upgrade for Phase II of the Gerda experiment

NASA Astrophysics Data System (ADS)

Agostini, M.; Bakalyarov, A. M.; Balata, M.; Barabanov, I.; Baudis, L.; Bauer, C.; Bellotti, E.; Belogurov, S.; Belyaev, S. T.; Benato, G.; Bettini, A.; Bezrukov, L.; Bode, T.; Borowicz, D.; Brudanin, V.; Brugnera, R.; Caldwell, A.; Cattadori, C.; Chernogorov, A.; D'Andrea, V.; Demidova, E. V.; Di Marco, N.; Domula, A.; Doroshkevich, E.; Egorov, V.; Falkenstein, R.; Frodyma, N.; Gangapshev, A.; Garfagnini, A.; Grabmayr, P.; Gurentsov, V.; Gusev, K.; Hakenmüller, J.; Hegai, A.; Heisel, M.; Hemmer, S.; Hiller, R.; Hofmann, W.; Hult, M.; Inzhechik, L. V.; Ioannucci, L.; Janicskó Csáthy, J.; Jochum, J.; Junker, M.; Kazalov, V.; Kermaïdic, Y.; Kihm, T.; Kirpichnikov, I. V.; Kirsch, A.; Kish, A.; Klimenko, A.; Kneißl, R.; Knöpfle, K. T.; Kochetov, O.; Kornoukhov, V. N.; Kuzminov, V. V.; Laubenstein, M.; Lazzaro, A.; Lebedev, V. I.; Lehnert, B.; Lindner, M.; Lippi, I.; Lubashevskiy, A.; Lubsandorzhiev, B.; Lutter, G.; Macolino, C.; Majorovits, B.; Maneschg, W.; Medinaceli, E.; Miloradovic, M.; Mingazheva, R.; Misiaszek, M.; Moseev, P.; Nemchenok, I.; Nisi, S.; Panas, K.; Pandola, L.; Pelczar, K.; Pullia, A.; Ransom, C.; Riboldi, S.; Rumyantseva, N.; Sada, C.; Salamida, F.; Salathe, M.; Schmitt, C.; Schneider, B.; Schönert, S.; Schreiner, J.; Schütz, A.-K.; Schulz, O.; Schwingenheuer, B.; Selivanenko, O.; Shevchik, E.; Shirchenko, M.; Simgen, H.; Smolnikov, A.; Stanco, L.; Vanhoefer, L.; Vasenko, A. A.; Veresnikova, A.; von Sturm, K.; Wagner, V.; Wegmann, A.; Wester, T.; Wiesinger, C.; Wojcik, M.; Yanovich, E.; Zhitnikov, I.; Zhukov, S. V.; Zinatulina, D.; Zsigmond, A. J.; Zuber, K.; Zuzel, G.

2018-05-01

The Gerda collaboration is performing a sensitive search for neutrinoless double beta decay of ^{76}Ge at the INFN Laboratori Nazionali del Gran Sasso, Italy. The upgrade of the Gerda experiment from Phase I to Phase II has been concluded in December 2015. The first Phase II data release shows that the goal to suppress the background by one order of magnitude compared to Phase I has been achieved. Gerda is thus the first experiment that will remain "background-free" up to its design exposure (100 kg year). It will reach thereby a half-life sensitivity of more than 10^{26} year within 3 years of data collection. This paper describes in detail the modifications and improvements of the experimental setup for Phase II and discusses the performance of individual detector components.

40 CFR 80.45 - Complex emissions model.

Code of Federal Regulations, 2011 CFR

2011-07-01

...) VOCW% = Percentage change in winter VOC emissions from baseline levels (8) Phase II total VOC emissions... its domain Phase I = The years 1995-1999 Phase II = Year 2000 and beyond (b) Weightings and baselines... appropriate pollutant and Phase: Table 1—Normal and Higher Emitter Weightings for Exhaust Emissions Phase I...

Theta EEG dynamics of the error-related negativity.

PubMed

Trujillo, Logan T; Allen, John J B

2007-03-01

The error-related negativity (ERN) is a response-locked brain potential (ERP) occurring 80-100ms following response errors. This report contrasts three views of the genesis of the ERN, testing the classic view that time-locked phasic bursts give rise to the ERN against the view that the ERN arises from a pure phase-resetting of ongoing theta (4-7Hz) EEG activity and the view that the ERN is generated - at least in part - by a phase-resetting and amplitude enhancement of ongoing theta EEG activity. Time-domain ERP analyses were augmented with time-frequency investigations of phase-locked and non-phase-locked spectral power, and inter-trial phase coherence (ITPC) computed from individual EEG trials, examining time courses and scalp topographies. Simulations based on the assumptions of the classic, pure phase-resetting, and phase-resetting plus enhancement views, using parameters from each subject's empirical data, were used to contrast the time-frequency findings that could be expected if one or more of these hypotheses adequately modeled the data. Error responses produced larger amplitude activity than correct responses in time-domain ERPs immediately following responses, as expected. Time-frequency analyses revealed that significant error-related post-response increases in total spectral power (phase- and non-phase-locked), phase-locked power, and ITPC were primarily restricted to the theta range, with this effect located over midfrontocentral sites, with a temporal distribution from approximately 150-200ms prior to the button press and persisting up to 400ms post-button press. The increase in non-phase-locked power (total power minus phase-locked power) was larger than phase-locked power, indicating that the bulk of the theta event-related dynamics were not phase-locked to response. Results of the simulations revealed a good fit for data simulated according to the phase-locking with amplitude enhancement perspective, and a poor fit for data simulated according to the classic view and the pure phase-resetting view. Error responses produce not only phase-locked increases in theta EEG activity, but also increases in non-phase-locked theta, both of which share a similar topography. The findings are thus consistent with the notion advanced by Luu et al. [Luu P, Tucker DM, Makeig S. Frontal midline theta and the error-related negativity; neurophysiological mechanisms of action regulation. Clin Neurophysiol 2004;115:1821-35] that the ERN emerges, at least in part, from a phase-resetting and phase-locking of ongoing theta-band activity, in the context of a general increase in theta power following errors.

Multinational Limited Objective Experiment II (MN LOE II)

DTIC Science & Technology

2003-06-01

multinational ONA development to the international players for the first time. Vignette 4 promoted the systems-of-systems approach , the need to...as a result of ongoing famines and economic chaos. The new nation adopted the South Korean form of government and economic system. Concern of a...negative impact on the economy of the south , as they combined with the north, was well founded. Without a Korean “Marshall Plan” instituted by the

Chesapeake Bay Low Freshwater Inflow Study. Phase II. MAP FOLIO. Biota Assessment.

DTIC Science & Technology

1982-05-01

conditions. These were: 1) Base Average -- average freshwater inflow conditions. by increased water consumption projected for the year 2020. 3) Base Drought...RESOLUTION TEST CHART NATIONAL BUREAU OF STANDARDS. 1963- A TAI m - ii J May 1982 Chesapeake Bay Low Freshwater Inflow Study Phase II Biota Assessment Map...A PERIOD ZOVERED change was found to CIESAPEAKE BAY LOW FRESHWATER INFLOW STUDY FINAL BIOTA ASSESSMENT PHASE II: FINAL REPORT MAP FOLIO s PERFORMING

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

PubMed Central

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

2013-01-01

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

47 CFR 54.310 - Connect America Fund for Price Cap Territories-Phase II

Code of Federal Regulations, 2014 CFR

2014-10-01

... 47 Telecommunication 3 2014-10-01 2014-10-01 false Connect America Fund for Price Cap Territories... Connect America Fund for Price Cap Territories—Phase II (a) Geographic areas eligible for support. Connect America Phase II support may be made available for census blocks or other areas identified as eligible by...

Stop Stroke: development of an innovative intervention to improve risk factor management after stroke.

PubMed

Redfern, Judith; Rudd, Anthony D; Wolfe, Charles D A; McKevitt, Christopher

2008-08-01

Stroke survivors are at high risk of stroke recurrence yet current strategies to reduce recurrence risk are sub-optimal. The UK Medical Research Council (MRC) have proposed a framework for developing and evaluating complex interventions, such as community management of stroke secondary prevention. The Framework outlines a five-phased approach from theory through to implementation of effective interventions. This paper reports Phases I-III of the development of a novel intervention to improve risk factor management after stroke. The pre-clinical/theoretical phase entailed reviewing the literature and undertaking quantitative and qualitative studies to identify current practices and barriers to secondary prevention. In Phase I (modelling), findings were used to design an intervention with the potential to overcome barriers to effective stroke secondary prevention management. The feasibility of delivering the intervention and its acceptability were tested in the Phase II exploratory trial involving 25 stroke survivors and their general practitioners. This led to the development of the definitive risk factor management intervention. This comprises multiple components and involves using an on-going population stroke register to target patients, carers and health care professionals with tailored secondary prevention advice. Clinical, socio-demographic and service use data collected by the stroke register are transformed to provide an individualised secondary prevention package for patients, carers and health care professionals at three time points: within 10 weeks, 3 and 6 months post-stroke. The intervention is currently being evaluated in a randomised controlled trial. Further research is needed to test generalisability to other aspects of stroke management and for other chronic diseases. The MRC Framework for complex interventions provides a structured approach to guide the development of novel interventions in public health. Implications for practice in stroke secondary prevention will emerge when the results of our randomised controlled trial are published.

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

Raman Frequencies Calculated from the Volume Data as a Function of Temperature at High Pressures for the Disordered Phase II of NH4I

NASA Astrophysics Data System (ADS)

Yurtseven, H.; Kavruk, D.

In this study, we calculate the Raman frequencies as a function of temperature for the fixed pressures of 706, 1080 and 6355 bars using the volume data for phase II of ammonium iodide. The Raman frequencies calculated here are for the translational optic ν5 TOM (125 cm-1) lattice mode that is located at the zone boundary (M point) of the Brillouin zone of phase II for NH4I. For this calculation the volume data obtained at zero pressure, is used through the mode Grüneisen parameter for the disordered phase II (β phase) which has the CsCl structure of NH4I. Our predicted frequencies of the ν5 TOM (125 cm-1) mode can be compared when the Raman data for this lattice mode is available at various temperatures for fixed pressures of 706, 1080 and 6355 bars in the disordered phase II of ammonium iodide.

Subliminal stimuli modulate somatosensory perception rhythmically and provide evidence for discrete perception

PubMed Central

Baumgarten, Thomas J.; Königs, Sara; Schnitzler, Alfons; Lange, Joachim

2017-01-01

Despite being experienced as continuous, there is an ongoing debate if perception is an intrinsically discrete process, with incoming sensory information treated as a succession of single perceptual cycles. Here, we provide causal evidence that somatosensory perception is composed of discrete perceptual cycles. We used in humans an electrotactile temporal discrimination task preceded by a subliminal (i.e., below perceptual threshold) stimulus. Although not consciously perceived, subliminal stimuli are known to elicit neuronal activity in early sensory areas and modulate the phase of ongoing neuronal oscillations. We hypothesized that the subliminal stimulus indirectly, but systematically modulates the ongoing oscillatory phase in S1, thereby rhythmically shaping perception. The present results confirm that, without being consciously perceived, the subliminal stimulus critically influenced perception in the discrimination task. Importantly, perception was modulated rhythmically, in cycles corresponding to the beta-band (13–18 Hz). This can be compellingly explained by a model of discrete perceptual cycles. PMID:28276493

Phase II Study of Adjuvant Immunotherapy with the CSF-470 Vaccine Plus Bacillus Calmette-Guerin Plus Recombinant Human Granulocyte Macrophage-Colony Stimulating Factor vs Medium-Dose Interferon Alpha 2B in Stages IIB, IIC, and III Cutaneous Melanoma Patients: A Single Institution, Randomized Study.

PubMed

Mordoh, José; Pampena, María Betina; Aris, Mariana; Blanco, Paula Alejandra; Lombardo, Mónica; von Euw, Erika María; Mac Keon, Soledad; Yépez Crow, Michelle; Bravo, Alicia Inés; O'Connor, Juan Manuel; Orlando, Ana Gabriela; Ramello, Franco; Levy, Estrella Mariel; Barrio, María Marcela

2017-01-01

The irradiated, allogeneic, cellular CSF-470 vaccine plus Bacillus Calmette-Guerin (BCG) and recombinant human granulocyte macrophage-colony stimulating factor (rhGM-CSF) is being tested against medium-dose IFN-α2b in stages IIB-III cutaneous melanoma (CM) patients (pts) after surgery in an open, randomized, Phase II/III study. We present the results of the Phase II part of the ongoing CASVAC-0401 study (ClinicalTrials.gov: NCT01729663). Thirty-one pts were randomized to the CSF-470 vaccine ( n  = 20) or to the IFN-α2b arm ( n  = 11). During the 2-year treatment, immunized pts should receive 13 vaccinations. On day 1 of each visit, 1.6 × 10 7 irradiated CSF-470 cells plus 10 6 colony-forming units BCG plus 100 µg rhGM-CSF were administered intradermally, followed on days 2-4 by 100 µg rhGM-CSF. IFN-α2b pts should receive 10 million units (MU)/day/5 days a week for 4 weeks; then 5 MU thrice weekly for 23 months. Toxicity and quality of life (QOL) were evaluated at each visit. With a mean and a maximum follow-up of 39.4 and 83 months, respectively, a significant benefit in the distant metastasis-free survival (DMFS) for CSF-470 was observed ( p  = 0.022). Immune monitoring showed an increase in antitumoral cellular and humoral response in vaccinated pts. CSF-470 was well tolerated; 20/20 pts presented grades 1-2 dermic reactions at the vaccination site; 3/20 pts presented grade 3 allergic reactions. Other adverse events (AEs) were grade 1. Pts in the IFN-α2b arm presented grades 2-3 hematological (7/11), hepatic (2/11), and cardiac (1/11) toxicity; AEs in 9/11 pts forced treatment interruptions. QOL was significantly superior in the vaccine arm ( p  < 0.0001). Our results suggest that CSF-470 vaccine plus BCG plus GM-CSF can significantly prolong, with lower toxicity, the DMFS of high-risk CM pts with respect to medium-dose IFN-α2b. The continuation of a Phase III part of the CASVAC-0401 study is encouraged.

Community partnership for healthy sleep: Research protocol.

PubMed

Redeker, Nancy S; Ordway, Monica R; Banasiak, Nancy; Caldwell, Barbara; Canapari, Craig; Crowley, Angela; Fenick, Ada; Jeon, Sangchoon; O'Connell, Meghan; Sude, Leslie; Sadler, Lois S

2018-02-01

Beginning early in life, sleep health, including adequate quality, quantity, and consistent sleep routines, is critical to growth and development, behavior, and mental and physical health. Children who live in economically stressed urban environments are at particular risk for sleep deficiency and its negative consequences. Although efficacious sleep health interventions are available, few address the context of economically stressed urban environments. The purpose of this paper is to describe a two-phase protocol for an ongoing NIH/NINR-funded community-engaged study designed to understand the perspectives of parents, community child care and pediatric health care providers about sleep habits, factors that contribute to sleep and sleep habits, sleep difficulty, and potentially useful sleep promotion strategies among children living in economically stressed urban environments. The social-ecological model guides this study. Phase I employs a convergent mixed-methods design, in which we are conducting semi-structured interviews with parents, childcare providers, and primary health care providers. We are collecting 9 days of objective sleep data (wrist actigraphy) from children who are 6-18 months (n = 15) and 19-36 months of age (n = 15) and parent reports of sleep and sleep-related factors using standard questionnaires. In Phase I, we will use a qualitative descriptive approach to analyze the interview data, and descriptive statistics to analyze the survey and actigraph data. In Phase II, we will use the information to develop a contextually relevant program to promote sleep health. Our long-term goal is to improve sleep health and sleep-related outcomes in these children. © 2017 Wiley Periodicals, Inc.

Technology evaluation: adalimumab, Abbott laboratories.

PubMed

Lorenz, Hanns M

2002-04-01

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

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

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

Keller, Carl J.

2004-07-13

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

[Incidence and preventability of adverse events in patients hospitalised in three Colombian hospitals during 2006].

PubMed

Gaitán-Duarte, Hernando; Eslava-Schmalbach, Javier; Rodríguez-Malagon, Nelcy; Forero-Supelano, Víctor; Santofimio-Sierra, Dagoberto; Altahona, Hernando

2008-01-01

Determining adverse event (AE) incidence, preventability, classification and impact for establishing their importance as a public health problem within the Colombian Social Security System. This was a study of a prospective inpatient cohort from three Colombian general-practice institutions. at least 12 hours' length of hospital stay during 2006. suffering psychiatric disorders and AE which had occurred before hospitalisation indexing. The sample consisted of 6 557 patients. clinical charts. Being a three-phase design, the first phase consisted of translating and standardising screening and causation formats, phase II of actively monitoring screening criteria and phase III of evaluating causation regarding the care being provided, based on specialist committee concept on a 0-6 scale. The variables measured were age, gender, social security affiliation, cumulative AE incidence, temporality, preventability of AE and disability resulting from them. 6,688 patients were evaluated; 505 of them fulfilled positive screening criteria (95 % CI=7,9;7,3-8,6), 310 presented at least one AE during their hospitalisation (95 %CI for accumulated incidence=4,6; 4,1-5,1). AE were considered to have been preventable in 189 cases (95 % CI=61;55-66) and permanent disability occurred in 1,3 % of them. AE-associated mortality was 6,4 % (20/310). Hospitalisation became increased to 1 072 days as a direct consequence of AE. This study revealed an important incidence of AE in three Colombian hospitals, these being mainly preventable. Their ongoing monitoring as a part of risk management systems could reduce costs and AE-associated morbidity and mortality.

Adaptive Randomization of Neratinib in Early Breast Cancer

PubMed Central

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

2017-01-01

Background I-SPY2, a standing, multicenter, adaptive phase 2 neoadjuvant trial ongoing in high-risk clinical stage II/III breast cancer, is designed to evaluate multiple, novel experimental agents added to standard chemotherapy for their ability to improve the rate of pathologic complete response (pCR). Experimental therapies are compared against a common control arm. We report efficacy for the tyrosine kinase inhibitor neratinib. Methods Eligible women had ≥2.5 cm stage II/III breast cancer, categorized into 8 biomarker subtypes based on HER2, hormone-receptor status (HR), and MammaPrint. Neratinib was evaluated for 10 signatures (prospectively defined subtype combinations), with primary endpoint pCR. MR volume changes inform likelihood of pCR for each patient prior to surgery. Adaptive assignment to experimental arms within disease subtype was based on current Bayesian probabilities of superiority over control. Accrual to experimental arm stop at any time for futility or graduation within a particular signature based on Bayesian predictive probability of success in a confirmatory trial. The maximum sample size in any experimental arm is 120 patients, Results With 115 patients and 78 concurrently randomized controls, neratinib graduated in the HER2+/HR− signature, with mean pCR rate 56% (95% PI: 37 to 73%) vs 33% for controls (11 to 54%). Final predictive probability of success, updated when all pathology data were available, was 79%. Conclusion Adaptive, multi-armed trials can efficiently identify responding tumor subtypes. Neratinib added to standard therapy is highly likely to improve pCR rates in HER2+/HR2212; breast cancer. Confirmation in I-SPY 3, a phase 3 neoadjuvant registration trial, is planned. PMID:27406346

Efficacy and safety of the human anti-IL-1beta monoclonal antibody canakinumab in rheumatoid arthritis: results of a 12-week, phase II, dose-finding study

PubMed Central

2011-01-01

Background Canakinumab is a fully human anti-interleukin IL-1beta monoclonal antibody, being investigated for the treatment of rheumatoid arthritis (RA). This multicenter, phase II, randomized, double-blind, placebo-controlled, parallel-group, dose-finding study investigated the efficacy and safety of canakinumab in patients with active RA despite ongoing therapy at stable doses of methotrexate. Methods Patients were randomized to receive one of four regimens, in addition to methotrexate, for 12 weeks: canakinumab 150 mg subcutaneously (SC) every 4 weeks (q4wk), canakinumab 300 mg SC (2 injections of 150 mg SC) every 2 weeks, a 600 mg intravenous loading dose of canakinumab followed by 300 mg SC every 2 weeks', or placebo SC every 2 weeks. Results Among 274 patients with evaluable efficacy data, the percentage of responders according to American College of Rheumatology 50 criteria (the primary endpoint, based on a 28-joint count) was significantly higher with canakinumab 150 mg SC q4wk than with placebo (26.5% vs. 11.4%, respectively; p = 0.028). Compared to placebo, this dosage of canakinumab was also associated with significantly more favorable responses at week 12 with respect to secondary endpoints including the Disease Activity Score 28, scores on the Health Assessment Questionnaire and Functional Assessment of Chronic Illness Therapy-Fatigue, swollen 28-joint count, and patient's and physician's global assessments of disease activity. No safety concerns were raised with canakinumab therapy, particularly with regard to infections. Few injection-site reactions occurred. Conclusion The addition of canakinumab 150 mg SC q4wk improves therapeutic responses among patients who have active RA despite stable treatment with methotrexate. Trial Registration (ClinicalTrials.gov identifier: NCT00784628) PMID:21736751

The National Geographic Names Data Base: Phase II instructions

USGS Publications Warehouse

Orth, Donald J.; Payne, Roger L.

1987-01-01

not recorded on topographic maps be added. The systematic collection of names from other sources, including maps, charts, and texts, is termed Phase II. In addition, specific types of features not compiled during Phase I are encoded and added to the data base. Other names of importance to researchers and users, such as historical and variant names, are also included. The rules and procedures for Phase II research, compilation, and encoding are contained in this publication.

Mixed response and time-to-event endpoints for multistage single-arm phase II design.

PubMed

Lai, Xin; Zee, Benny Chung-Ying

2015-06-04

The objective of phase II cancer clinical trials is to determine if a treatment has sufficient activity to warrant further study. The efficiency of a conventional phase II trial design has been the object of considerable debate, particularly when the study regimen is characteristically cytostatic. At the time of development of a phase II cancer trial, we accumulated clinical experience regarding the time to progression (TTP) for similar classes of drugs and for standard therapy. By considering the time to event (TTE) in addition to the tumor response endpoint, a mixed-endpoint phase II design may increase the efficiency and ability of selecting promising cytotoxic and cytostatic agents for further development. We proposed a single-arm phase II trial design by extending the Zee multinomial method to fully use mixed endpoints with tumor response and the TTE. In this design, the dependence between the probability of response and the TTE outcome is modeled through a Gaussian copula. Given the type I and type II errors and the hypothesis as defined by the response rate (RR) and median TTE, such as median TTP, the decision rules for a two-stage phase II trial design can be generated. We demonstrated through simulation that the proposed design has a smaller expected sample size and higher early stopping probability under the null hypothesis than designs based on a single-response endpoint or a single TTE endpoint. The proposed design is more efficient for screening new cytotoxic or cytostatic agents and less likely to miss an effective agent than the alternative single-arm design.

Outcome assessment of patients undergoing maxillofacial procedures for the treatment of sleep apnea: comparison of subjective and objective results.

PubMed

Dattilo, David J; Drooger, Scott A

2004-02-01

The purpose of this study was to compare the subjective findings of the Epworth Sleepiness Scale (ESS) to the objective findings of the overnight sleep study (OSS) in 57 patients who underwent phase I and phase II surgery for the correction of obstructive sleep apnea (OSA). Forty-two patients in phase I category (hyoid suspension, palatal surgery, and/or genioglossus advancement) and 15 patients in phase II category (maxillomandibular advancement) were examined. All patients had an OSS and completion of an ESS preoperatively and at a minimum of 8 weeks postoperatively. The results of each test were evaluated to examine any relationship between the improvements of the findings of the OSS to the changes in the ESS. Using accepted criteria, phase I surgery produced an 80% success rate and phase II surgery produced a greater than 95% success rate in both the respiratory disturbance index and the ESS. 1) Both phase I and phase II procedures are effective in treating OSA. 2) Phase II appears to be more effective in treating OSA using both objective and subjective evaluations. 3) Improvement in ESS scores and excessive daytime sleepiness seems to parallel the improvement in OSS scores in patients undergoing surgical correction of OSA.

A Fire Safety Certification System for Board and Care Operators and Staff. SBIR Phase II: Final Report.

ERIC Educational Resources Information Center

Walker, Bonnie L.

This report describes Phase II of a project which developed a system for delivering fire safety training to board and care providers who serve adults with developmental disabilities. Phase II focused on developing and pilot testing a "train the trainers" workshop for instructors and field testing the provider's workshop. Evaluation of…

Single-arm phase II trial design under parametric cure models.

PubMed

Wu, Jianrong

2015-01-01

The current practice of designing single-arm phase II survival trials is limited under the exponential model. Trial design under the exponential model may not be appropriate when a portion of patients are cured. There is no literature available for designing single-arm phase II trials under the parametric cure model. In this paper, a test statistic is proposed, and a sample size formula is derived for designing single-arm phase II trials under a class of parametric cure models. Extensive simulations showed that the proposed test and sample size formula perform very well under different scenarios. Copyright © 2015 John Wiley & Sons, Ltd.

Exploring mechanisms of fatigue during repeated exercise and the dose dependent effects of carbohydrate and protein ingestion: study protocol for a randomised controlled trial

PubMed Central

2014-01-01

Background Muscle glycogen has been well established as the primary metabolic energy substrate during physical exercise of moderate- to high-intensity and has accordingly been implicated as a limiting factor when such activity is sustained for a prolonged duration. However, the role of this substrate during repeated exercise after limited recovery is less clear, with ongoing debate regarding how recovery processes can best be supported via nutritional intervention. The aim of this project is to examine the causes of fatigue during repeated exercise bouts via manipulation of glycogen availability through nutritional intervention, thus simultaneously informing aspects of the optimal feeding strategy for recovery from prolonged exercise. Methods/Design The project involves two phases with each involving two treatment arms administered in a repeated measures design. For each treatment, participants will be required to exercise to the point of volitional exhaustion on a motorised treadmill at 70% of previously determined maximal oxygen uptake, before a four hour recovery period in which participants will be prescribed solutions providing 1.2 grams of sucrose per kilogram of body mass per hour of recovery (g.kg-1.h-1) relative to either a lower rate of sucrose ingestion (that is, 0.3 g.kg-1. h-1; Phase I) or a moderate dose (that is, 0.8 g.kg-1.h-1) rendered isocaloric via the addition of 0.4 g.kg-1.h-1 whey protein hydrolysate (Phase II); the latter administered in a double blind manner as part of a randomised and counterbalanced design. Muscle biopsies will be sampled at the beginning and end of recovery for determination of muscle glycogen resynthesis rates, with further biopsies taken following a second bout of exhaustive exercise to determine differences in substrate availability relative to the initial sample taken following the first exercise bout. Discussion Phase I will inform whether a dose–response relationship exists between carbohydrate ingestion rate and muscle glycogen availability and/or the subsequent capacity for physical exercise. Phase II will determine whether such effects are dependent on glycogen availability per se or energy intake, potentially via protein mediated mechanisms. Trial registration ISRCTN87937960. PMID:24670140

Wellness-Promoting Practices Through Girl Scouts: A Pragmatic Superiority Randomized Controlled Trial With Additional Dissemination.

PubMed

Cull, Brooke J; Dzewaltowski, David A; Guagliano, Justin M; Rosenkranz, Sara K; Knutson, Cassandra K; Rosenkranz, Richard R

2018-01-01

To evaluate the effectiveness of in-person versus online Girl Scout leader wellness training for implementation of wellness-promoting practices during troop meetings (phase I) and to assess training adoption and current practices across the council (phase II). Pragmatic superiority trial (phase 1) followed by serial cross-sectional study (phase II). Girl Scout troop meetings in Northeast Kansas. Eighteen troop leaders from 3 counties (phase 1); 113 troop leaders from 7 counties (phase II). Phase I: Troop leaders attended 2 wellness training sessions (first in groups, second individually), wherein leaders set wellness-promoting practice implementation goals, self-monitored progress, and received guidance and resources for implementation. Leaders received the intervention in person or online. Phase I: At baseline and postintervention, leaders completed a wellness-promoting practice implementation questionnaire assessing practices during troop meetings (max score = 11). Phase II: Leaders completed a survey about typical troop practices and interest in further training. Phase I: Generalized linear mixed modeling. Phase I: In-person training increased wellness-promoting practice implementation more than online training (in person = 2.1 ± 1.8; online = 0.2 ± 1.2; P = .022). Phase II: Fifty-six percent of leaders adopted the training. For 8 of 11 wellness categories, greater than 50% of leaders employed wellness-promoting practices. In-person training was superior to online training for improvements in wellness-promoting practices. Wellness training was adopted by the majority of leaders across the council.

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

Starcher, Autumn N.; Elzinga, Evert J.; Sparks, Donald L.

Previous research demonstrated the formation of single divalent metal (Co, Ni, and ZnAl) and mixed divalent metal (NiZnAl) layered double hydroxide (LDH) phases from reactions of the divalent metal with Al-bearing substrates and soils in both laboratory experiments and in the natural environment. Recently Fe(II)-Al-LDH phases have been found in laboratory batch reaction studies, and although they have yet to be found in the natural environment. Potential locations of Fe(II)-Al-LDH phases in nature include areas with suboxic and anoxic conditions. Because these areas can be environments of significant contaminant accumulation, it is important to understand the possible interactions and impactsmore » of contaminant elements on LDH phase formation. One such contaminant, Zn, can also form as an LDH and has been found to form as a mixed divalent layered hydroxide phase. To understand how Zn impacts the formation of Fe(II)-Al-LDH phase formation and kinetics, 3 mM or 0.8 mM Fe(II) and 0.8 mM Zn were batch reacted with either 10 g/L pyrophyllite or 7.5 g/L γ-Al2O3 for up to three months under anoxic conditions. Aqueous samples were analyzed by inductively coupled plasma optical emission spectrometry (ICP-OES) and solid samples were analyzed with X-ray absorption spectroscopy (XAS). Shell-by-shell fits of Fe(II) and co-sorption samples with pyrophyllite show the formation of a mixed divalent metal (Fe(II)-Zn-Al) layered hydroxide phase, while Fe(II) and Zn co-sorption samples with γ-Al2O3 produce Fe(II)-Al-LDH phases and Zn in inner-sphere complexation with the γ-Al2O3. This study demonstrates the formation of a mixed divalent metal layered hydroxide and further iterates the importance of sorbent reactivity on LDH phase formation.« less

Neratinib, A Novel HER2-Targeted Tyrosine Kinase Inhibitor.

PubMed

Tiwari, Shruti Rakesh; Mishra, Prasun; Abraham, Jame

2016-10-01

HER2 gene amplification and receptor overexpression is identified in 20% to 25% of human breast cancers. Use of targeted therapy for HER2-amplified breast cancer has led to improvements in disease-free and overall survival in this subset of patients. Neratinib is an oral pan HER inhibitor, that irreversibly inhibits the tyrosine kinase activity of epidermal growth factor receptor (EGFR or HER1), HER2, and HER4, which leads to reduced phosphorylation and activation of downstream signaling pathways. Neratinib is currently being tested in a number of clinical trials for its safety and efficacy in lung cancer, and colorectal, bladder, and breast cancers. In this review we discuss the available phase I, II, and III data for use of neratinib in the metastatic, adjuvant, neoadjuvant, and extended adjuvant settings along with the ongoing clinical trials of neratinib in breast cancer. We also elaborate on the side effect profile of this relatively new drug and provide guidelines for its use in clinical practice. Copyright © 2016 Elsevier Inc. All rights reserved.

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

PubMed Central

Costello, Caitlin

2016-01-01

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

The role of human papillomavirus vaccines in cervical neoplasia.

PubMed

Stern, P L; Faulkner, R; Veranes, E C; Davidson, E J

2001-10-01

Cervical cancer is the second most common cause of cancer-related death in women, in some developing countries accounting for the highest cancer mortality. The evidence for the association of high-risk human papillomavirus types with the aetiology of cervical neoplasia is firmly established, human papillomavirus being detected in virtually all cervical cancers. The risk of progression of precursor cervical intra-epithelial neoplasia lesions is associated with persistence of human papillomavirus infection. One strategy for the management of cervical neoplasia worldwide could be the development of prophylactic and/or therapeutic human papillomavirus vaccines. This chapter will discuss the natural history of human papillomavirus infection, viral immunity and the clinical course of resultant disease as the background to the effective design and use of human papillomavirus vaccines for protection or therapy. The progress of ongoing phase I and II clinical trials for several different vaccine preparations and the challenges for establishing their future use will be discussed. Copyright 2001 Harcourt Publishers Ltd.

Nuclear Thermal Rocket Element Environmental Simulator (NTREES) Phase II Upgrade Activities

NASA Technical Reports Server (NTRS)

Emrich, William J.; Moran, Robert P.; Pearson, J. Bose

2013-01-01

To support the on-going nuclear thermal propulsion effort, a state-of-the-art non nuclear experimental test setup has been constructed to evaluate the performance characteristics of candidate fuel element materials and geometries in representative environments. The facility to perform this testing is referred to as the Nuclear Thermal Rocket Element Environment Simulator (NTREES). This device can simulate the environmental conditions (minus the radiation) to which nuclear rocket fuel components will be subjected during reactor operation. Test articles mounted in the simulator are inductively heated in such a manner so as to accurately reproduce the temperatures and heat fluxes which would normally occur as a result of nuclear fission and would be exposed to flowing hydrogen. Initial testing of a somewhat prototypical fuel element has been successfully performed in NTREES and the facility has now been shutdown to allow for an extensive reconfiguration of the facility which will result in a significant upgrade in its capabilities. Keywords: Nuclear Thermal Propulsion, Simulator

Visual Invention and the Composition of Scientific Research Graphics: A Topological Approach

ERIC Educational Resources Information Center

Walsh, Lynda

2018-01-01

This report details the second phase of an ongoing research project investigating the visual invention and composition processes of scientific researchers. In this phase, four academic researchers completed think-aloud protocols as they composed graphics for research presentations; they also answered follow-up questions about their visual…

Emerging drugs for hemophilia B.

PubMed

Mannucci, Pier Mannuccio; Franchini, Massimo

2014-09-01

Hemophilia B is a rare congenital bleeding disorder characterized by a deficiency of coagulation factor IX (FIX). Hemophilia B patients experience mild-to-severe bleeding complications according to the degree of FIX defect. Prophylaxis, with regular infusion of FIX concentrates, is nowadays, the mainstay of hemophilia care. However, because the relatively short half-life of such products necessitates frequent infusions and thus makes patients' adherence difficult, a number of strategies have been implemented to improve the pharmacokinetics of FIX clotting factors. This review summarizes the main results of Phase I/II and III studies on new FIX molecules engineered to have a longer half-life. Several technologies are being applied to extend FIX half-life, including Fc fusion, recombinant (r) albumin fusion and the addition of PEG polymers. By prolonging the FIX half-life up to 5 times, long-acting FIX products are expected to substantially improve the management of hemophilia B patients, allowing less frequent infusions and improving patients' adherence to prophylactic regimens and individualized treatments. Some of them are at an advanced stage of development, such as the rFIX-Fc which has been launched in March 2014. Along with the ongoing Phase III trials, long-term post-marketing surveillance studies are needed to assess their safety and effectiveness and their impact on patients' quality of life.

A Socio-Technical Exploration for Reducing & Mitigating the Risk of Retained Foreign Objects

PubMed Central

Corrigan, Siobhán; Kay, Alison; O’Byrne, Katie; Slattery, Dubhfeasa; Sheehan, Sharon; McDonald, Nick; Smyth, David; Mealy, Ken; Cromie, Sam

2018-01-01

A Retained Foreign Object (RFO) is a fairly infrequent but serious adverse event. An accurate rate of RFOs is difficult to establish due to underreporting but it has been estimated that incidences range between 1/1000 and 1/19,000 procedures. The cost of a RFO incident may be substantial and three-fold: (i) the cost to the patient of physical and/or psychological harm; (ii) the reputational cost to an institution and/or healthcare provider; and (iii) the financial cost to the taxpayer in the event of a legal claim. This Health Research Board-funded project aims to analyse and understand the problem of RFOs in surgical and maternity settings in Ireland and develop hospital-specific foreign object management processes and implementation roadmaps. This project will deploy an integrated evidence-based assessment methodology for social-technical modelling (Supply, Context, Organising, Process & Effects/ SCOPE Analysis Cube) and bow tie methodologies that focuses on managing the risks in effectively implementing and sustaining change. It comprises a multi-phase research approach that involves active and ongoing collaboration with clinical and other healthcare staff through each phase of the research. The specific objective of this paper is to present the methodological approach and outline the potential to produce generalisable results which could be applied to other health-related issues. PMID:29642646

Human utilization of subsurface extraterrestrial environments.

PubMed

Boston, P J; Frederick, R D; Welch, S M; Werker, J; Meyer, T R; Sprungman, B; Hildreth-Werker, V; Thompson, S L; Murphy, D L

2003-06-01

Caves have been used in the ancient past as shelter or habitat by many organisms (including humans). Since antiquity, humans have explored caves for the minerals they contain and sometimes for ceremonial purposes. Over the past century, caves have become the target of increasing exploration, scientific research, and recreation. The use of caves on extraterrestrial bodies for human habitation has been suggested by several investigators. Lunar lava tube bases received early attention because lava tubes were clearly visible in lunar images from the Apollo Era. More recently, Mars Observer Camera data has shown us clear evidence of large tubes visible in a number of volcanic regions on Mars. The budding field of cave geomicrobiology has direct application to questions about subsurface life on other planets. Caves contain many unusual organisms making their living from unlikely materials like manganese, iron, and sulfur. This makes caves and other subsurface habitats prime targets for astrobiological missions to Mars and possibly other bodies. We present the results of a completed Phase I and on-going Phase II NASA Institute for Advanced Concepts (NIAC) study that intensively examines the possibilities of using extraterrestrial caves as both a resource for human explorers and as a highly promising scientific target for both robotic and future human missions to Mars and beyond.

Peptide vaccine immunotherapy biomarkers and response patterns in pediatric gliomas

PubMed Central

Müller, Sören; Agnihotri, Sameer; Shoger, Karsen E.; Myers, Max I.; Chaparala, Srilakshmi; Villanueva, Clarence R.; Chattopadhyay, Ansuman; Butterfield, Lisa H.; Okada, Hideho; Pollack, Ian F.

2018-01-01

Low-grade gliomas (LGGs) are the most common brain tumor affecting children. We recently reported an early phase clinical trial of a peptide-based vaccine, which elicited consistent antigen-specific T cell responses in pediatric LGG patients. Additionally, we observed radiologic responses of stable disease (SD), partial response (PR), and near-complete/complete response (CR) following therapy. To identify biomarkers of clinical response in peripheral blood, we performed RNA sequencing on PBMC samples collected at multiple time points. Patients who showed CR demonstrated elevated levels of T cell activation markers, accompanied by a cytotoxic T cell response shortly after treatment initiation. At week 34, patients with CR demonstrated both IFN signaling and Poly-IC:LC adjuvant response patterns. Patients with PR demonstrated a unique, late monocyte response signature. Interestingly, HLA-V expression, before or during therapy, and an early monocytic hematopoietic response were strongly associated with SD. Finally, low IDO1 and PD-L1 expression before treatment and early elevated levels of T cell activation markers were associated with prolonged progression-free survival. Overall, our data support the presence of unique peripheral immune patterns in LGG patients associated with different radiographic responses to our peptide vaccine immunotherapy. Future clinical trials, including our ongoing phase II LGG vaccine immunotherapy, should monitor these response patterns. PMID:29618666

CMIF ECLS system test findings

NASA Technical Reports Server (NTRS)

Schunk, Richard G.; Carrasquillo, Robyn L.; Ogle, Kathyrn Y.; Wieland, Paul O.; Bagdigian, Robert M.

1989-01-01

During 1987 three Space Station integrated Environmental Control and Life Support System (ECLSS) tests were conducted at the Marshall Space Flight Center (MSFC) Core Module Integration Facility (CMIF) as part of the MSFC ECLSS Phase II test program. The three tests ranged in duration from 50 to 150 hours and were conducted inside of the CMIF module simulator. The Phase II partial integrated system test configuration consisted of four regenerative air revitalization subsystems and one regenerative water reclamation subsystem. This paper contains a discussion of results and lessons learned from the Phase II test program. The design of the Phase II test configuration and improvements made throughout the program are detailed. Future plans for the MSFC CMIF test program are provided, including an overview of planned improvements for the Phase III program.

Orthotopic liver transplantation in an adult with cholesterol ester storage disease.

PubMed

Ambler, Graeme K; Hoare, Matthew; Brais, Rebecca; Shaw, Ashley; Butler, Andrew; Flynn, Paul; Deegan, Patrick; Griffiths, William J H

2013-01-01

Cholesterol ester storage disease (CESD) is a rare autosomal recessive lipid storage disorder associated with mutations of the gene encoding lysosomal acid lipase, manifestations of which include chronic liver disease and early atherosclerosis. Although normally presenting in childhood, severity is variable and the condition can occasionally remain undetected until middle age. Typical presentation is with asymptomatic hepatosplenomegaly and hyperlipidaemia, though the condition is probably underdiagnosed. Treatment is supportive and may include attention to cardiovascular risk factors. Phase I/II trials of enzyme replacement therapy are ongoing, but this approach remains experimental. We present the case of a 42-year-old woman diagnosed with CESD in childhood who ran an indolent course until re-presentation with cirrhotic hydrothorax. She underwent orthotopic liver transplantation but required re-transplantation for hepatic artery thrombosis. She remains well with excellent graft function 2 years later. Although atherosclerosis was apparent at assessment, and may have contributed to hepatic artery thrombosis, partial correction of the metabolic defect and restoration of liver function by transplantation together with ongoing medical therapy should permit reasonable survival over the longer term from both a liver and a vascular perspective. This is the first reported case of orthotopic liver transplantation for CESD in an adult, which was the only available option to improve survival. The case highlights the importance of monitoring patients with CESD through adulthood and suggests that liver replacement at a later stage may yet be indicated and remain of benefit.

Investing in Our Nation's Youth. National Youth Anti-Drug Media Campaign: Phase II (Final Report).

ERIC Educational Resources Information Center

Office of National Drug Control Policy, Washington, DC.

This publication presents the findings from an evaluation of Phase II of the National Youth Anti-Drug Media Campaign. The number one goal of the campaign was to educate youth to reject illegal drugs. This report evaluates Phase II and focuses on the effect of paid television advertising on awareness of anti-drug messages among youth, teens, and…

Labeled carbon dioxide (C18O2): an indicator gas for phase II in expirograms.

PubMed

Schulz, Holger; Schulz, Anne; Eder, Gunter; Heyder, Joachim

2004-11-01

Carbon dioxide labeled with 18O (C18O2) was used as a tracer gas for single-breath measurements in six anesthetized, mechanically ventilated beagle dogs. C18O2 is taken up quasi-instantaneously in the gas-exchanging region of the lungs but much less so in the conducting airways. Its use allows a clear separation of phase II in an expirogram even from diseased individuals and excludes the influence of alveolar concentration differences. Phase II of a C18O2 expirogram mathematically corresponds to the cumulative distribution of bronchial pathways to be traversed completely in the course of exhalation. The derivative of this cumulative distribution with respect to respired volume was submitted to a power moment analysis to characterize volumetric mean (position), standard deviation (broadness), and skewness (asymmetry) of phase II. Position is an estimate of dead space volume, whereas broadness and skewness are measures of the range and asymmetry of functional airway pathway lengths. The effects of changing ventilatory patterns and of changes in airway size (via carbachol-induced bronchoconstriction) were studied. Increasing inspiratory or expiratory flow rates or tidal volume had only minor influence on position and shape of phase II. With the introduction of a postinspiratory breath hold, phase II was continually shifted toward the airway opening (maximum 45% at 16 s) and became steeper by up to 16%, whereas skewness showed a biphasic response with a moderate decrease at short breath holding and a significant increase at longer breath holds. Stepwise bronchoconstriction decreased position up to 45 +/- 2% and broadness of phase II up to 43 +/- 4%, whereas skewness was increased up to twofold at high-carbachol concentrations. Under all circumstances, position of phase II by power moment analysis and dead space volume by the Fowler technique agreed closely in our healthy dogs. Overall, power moment analysis provides a more comprehensive view on phase II of single-breath expirograms than conventional dead space volume determinations and may be useful for respiratory physiology studies as well as for the study of diseased lungs.

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

Downar, Thomas

This report summarizes the current status of VERA-CS Verification and Validation for PWR Core Follow operation and proposes a multi-phase plan for continuing VERA-CS V&V in FY17 and FY18. The proposed plan recognizes the hierarchical nature of a multi-physics code system such as VERA-CS and the importance of first achieving an acceptable level of V&V on each of the single physics codes before focusing on the V&V of the coupled physics solution. The report summarizes the V&V of each of the single physics codes systems currently used for core follow analysis (ie MPACT, CTF, Multigroup Cross Section Generation, and BISONmore » / Fuel Temperature Tables) and proposes specific actions to achieve a uniformly acceptable level of V&V in FY17. The report also recognizes the ongoing development of other codes important for PWR Core Follow (e.g. TIAMAT, MAMBA3D) and proposes Phase II (FY18) VERA-CS V&V activities in which those codes will also reach an acceptable level of V&V. The report then summarizes the current status of VERA-CS multi-physics V&V for PWR Core Follow and the ongoing PWR Core Follow V&V activities for FY17. An automated procedure and output data format is proposed for standardizing the output for core follow calculations and automatically generating tables and figures for the VERA-CS Latex file. A set of acceptance metrics is also proposed for the evaluation and assessment of core follow results that would be used within the script to automatically flag any results which require further analysis or more detailed explanation prior to being added to the VERA-CS validation base. After the Automation Scripts have been completed and tested using BEAVRS, the VERA-CS plan proposes the Watts Bar cycle depletion cases should be performed with the new cross section library and be included in the first draft of the new VERA-CS manual for release at the end of PoR15. Also, within the constraints imposed by the proprietary nature of plant data, as many as possible of the FY17 AMA Plant Core Follow cases should also be included in the VERA-CS manual at the end of PoR15. After completion of the ongoing development of TIAMAT for fully coupled, full core calculations with VERA-CS / BISON 1.5D, and after the completion of the refactoring of MAMBA3D for CIPS analysis in FY17, selected cases from the VERA-CS validation based should be performed, beginning with the legacy cases of Watts Bar and BEAVRS in PoR16. Finally, as potential Phase III future work some additional considerations are identified for extending the VERA-CS V&V to other reactor types such as the BWR.« less

Generation of phase II in vitro metabolites using homogenized horse liver.

PubMed

Wong, Jenny K Y; Chan, George H M; Leung, David K K; Tang, Francis P W; Wan, Terence S M

2016-02-01

The successful use of homogenized horse liver for the generation of phase I in vitro metabolites has been previously reported by the authors' laboratory. Prior to the use of homogenized liver, the authors' laboratory had been using mainly horse liver microsomes for carrying out equine in vitro metabolism studies. Homogenized horse liver has shown significant advantages over liver microsomes for in vitro metabolism studies as the procedures are much quicker and have higher capability for generating more in vitro metabolites. In this study, the use of homogenized liver has been extended to the generation of phase II in vitro metabolites (glucuronide and/or sulfate conjugates) using 17β-estradiol, morphine, and boldenone undecylenate as model substrates. It was observed that phase II metabolites could also be generated even without the addition of cofactors. To the authors' knowledge, this is the first report of the successful use of homogenized horse liver for the generation of phase II metabolites. It also demonstrates the ease with which both phase I and phase II metabolites can now be generated in vitro simply by using homogenized liver without the need for ultracentrifuges or tedious preparation steps. Copyright © 2015 John Wiley & Sons, Ltd.

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

Usability and safety of ventricular assist devices: human factors and design aspects.

PubMed

Geidl, Lorenz; Zrunek, Philipp; Deckert, Zeno; Zimpfer, Daniel; Sandner, Sigrid; Wieselthaler, Georg; Schima, Heinrich

2009-09-01

The purpose of this study was the investigation of the usability and ergonomics of ventricular assist devices (VADs) in everyday usage. Patients with four different VAD types were observed. After implantation, instruction, and discharge from the hospital, the patients returned on a regular basis to the outpatient clinic, where the investigation took place. Data collection took place in two phases. In phase I home-released VAD patients were asked about perceived problems with the system at home. Additionally health-care professionals were interviewed to gather information on frequent VAD inconveniences and shortcomings. This inquiry resulted in a standardized self-assessment questionnaire and a manual skill test, which were performed in phase II by the whole collective (16 patients and ongoing). As a result, 38% of the patients disconnected parts of their system unintentionally at least once. All of them ascribed this problem to their own carelessness. Thirty-eight percent had to replace a cable. Seventy-five percent desired an additional cable strain relief. Thirty-eight percent suffered from rubbing of parts on the body. Sixty-three percent used a separate repository aside from the factory-provided transportation systems. The overall noise emission (pump, ventilators, and alarms) annoyed 56%; however, for 32% the alarm signals were too quiet to wake them up. No correlation between the assessed manual skills and the number of adverse events was found. To conclude, this preliminary study revealed considerable potential for improvements in the usability of ventricular assist systems.

Phenotypic variation of Pseudomonas brassicacearum as a plant root-colonization strategy.

PubMed

Achouak, Wafa; Conrod, Sandrine; Cohen, Valérie; Heulin, Thierry

2004-08-01

Pseudomonas brassicacearum was isolated as a major root-colonizing population from Arabidopsis thaliana. The strain NFM421 of P. brassicacearum undergoes phenotypic variation during A. thaliana and Brassica napus root colonization in vitro as well as in soil, resulting in different colony appearance on agar surfaces. Bacteria forming translucent colonies (phase II cells) essentially were localized at the surface of young roots and root tips, whereas wild-type cells (phase I cells) were localized at the basal part of roots. The ability of phase II cells to spread and colonize new sites on root surface correlates with over-production of flagellin as evidenced by sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis of surface proteins and microsequencing. Moreover, phase II cells showed a higher ability to swim and to swarm on semisolid agar medium. Phase I and phase II cells of P. brassicacearum NFM421 were tagged genetically with green fluorescent protein and red fluorescent protein. Confocal scanning laser microscopy was used to localize phase II cells on secondary roots and root tips of A. thaliana, whereas phase I cells essentially were localized at the basal part of roots. These experiments were conducted in vitro and in soil. Phenotypic variation on plant roots is likely to be a colonization strategy that may explain the high colonization power of P. brassicacearum.

Escape of X-linked miRNA genes from meiotic sex chromosome inactivation

PubMed Central

Sosa, Enrique; Flores, Luis; Yan, Wei; McCarrey, John R.

2015-01-01

Past studies have indicated that transcription of all X-linked genes is repressed by meiotic sex chromosome inactivation (MSCI) during the meiotic phase of spermatogenesis in mammals. However, more recent studies have shown an increase in steady-state levels of certain X-linked miRNAs in pachytene spermatocytes, suggesting that either synthesis of these miRNAs increases or that degradation of these miRNAs decreases dramatically in these cells. To distinguish between these possibilities, we performed RNA-FISH to detect nascent transcripts from multiple miRNA genes in various spermatogenic cell types. Our results show definitively that Type I X-linked miRNA genes are subject to MSCI, as are all or most X-linked mRNA genes, whereas Type II and III X-linked miRNA genes escape MSCI by continuing ongoing, active transcription in primary spermatocytes. We corroborated these results by co-localization of RNA-FISH signals with both a corresponding DNA-FISH signal and an immunofluorescence signal for RNA polymerase II. We also found that X-linked miRNA genes that escape MSCI locate non-randomly to the periphery of the XY body, whereas genes that are subject to MSCI remain located within the XY body in pachytene spermatocytes, suggesting that the mechanism of escape of X-linked miRNA genes from MSCI involves their relocation to a position outside of the repressive chromatin domain associated with the XY body. The fact that Type II and III X-linked miRNA genes escape MSCI suggests an immediacy of function of the encoded miRNAs specifically required during the meiotic stages of spermatogenesis. PMID:26395485

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.

Spiral chain structure of high pressure selenium-II{sup '} and sulfur-II from powder x-ray diffraction

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

Fujihisa, Hiroshi; Yamawaki, Hiroshi; Sakashita, Mami

2004-10-01

The structure of high pressure phases, selenium-II{sup '} (Se-II{sup '}) and sulfur-II (S-II), for {alpha}-Se{sub 8} (monoclinic Se-I) and {alpha}-S{sub 8} (orthorhombic S-I) was studied by powder x-ray diffraction experiments. Se-II{sup '} and S-II were found to be isostructural and to belong to the tetragonal space group I4{sub 1}/acd, which is made up of 16 atoms in the unit cell. The structure consisted of unique spiral chains with both 4{sub 1} and 4{sub 3} screws. The results confirmed that the structure sequence of the pressure-induced phase transitions for the group VIb elements depended on the initial molecular form. The chemicalmore » bonds of the phases are also discussed from the interatomic distances that were obtained.« less

Hazardous materials safety and security technology field operational test. Volume II, evaluation final report synthesis

DOT National Transportation Integrated Search

2004-11-11

The catastrophic events of September 11, 2001 and the ongoing war on terrorism have heightened the level of concern from Federal government officials and the transportation industry regarding the secure transport of hazardous materials (HAZMAT). Secu...

22 CFR 216.2 - Applicability of procedures.

Code of Federal Regulations, 2010 CFR

2010-04-01

... river basin development; (ii) Irrigation or water management projects, including dams and impoundments... projects, programs or activities authorized or approved by A.I.D. and to substantive amendments or extensions of ongoing projects, programs, or activities. (b) Exemptions. (1) Projects, programs or activities...

Fire Prevention Posters: The Story of Smokey Bear. Teaching with Documents.

ERIC Educational Resources Information Center

Haverkamp, Beth; Schamel, Wynell B.

1994-01-01

Contends that, despite increasingly sophisticated means of communication, posters remain a powerful cornerstone of many government advertising campaigns. Describes the beginnings and evolution of Smokey Bear from a World War II homefront poster to an ongoing advertising success. (CFR)

The Origins of [C ii] Emission in Local Star-forming Galaxies

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

Croxall, K. V.; Smith, J. D.; Pellegrini, E.

The [C ii] 158 μ m fine-structure line is the brightest emission line observed in local star-forming galaxies. As a major coolant of the gas-phase interstellar medium, [C ii] balances the heating, including that due to far-ultraviolet photons, which heat the gas via the photoelectric effect. However, the origin of [C ii] emission remains unclear because C{sup +} can be found in multiple phases of the interstellar medium. Here we measure the fractions of [C ii] emission originating in the ionized and neutral gas phases of a sample of nearby galaxies. We use the [N ii] 205 μ m fine-structuremore » line to trace the ionized medium, thereby eliminating the strong density dependence that exists in the ratio of [C ii]/[N ii] 122 μ m. Using the FIR [C ii] and [N ii] emission detected by the KINGFISH (Key Insights on Nearby Galaxies: a Far- Infrared Survey with Herschel ) and Beyond the Peak Herschel programs, we show that 60%–80% of [C ii] emission originates from neutral gas. We find that the fraction of [C ii] originating in the neutral medium has a weak dependence on dust temperature and the surface density of star formation, and has a stronger dependence on the gas-phase metallicity. In metal-rich environments, the relatively cooler ionized gas makes substantially larger contributions to total [C ii] emission than at low abundance, contrary to prior expectations. Approximate calibrations of this metallicity trend are provided.« less

Beginning Teacher Evaluation Study: Phase II, 1973-74, Final Report: Volume III.2. Reading and Mathematics Observation System: Description and Analysis of Time Expenditures.

ERIC Educational Resources Information Center

Calfee, Robert; Calfee, Kathryn Hoover

The Beginning Teacher Evaluation Study (BTES), Phase II, was a research project on effective teaching behavior--what teachers do that significantly affects what and how pupils learn. The purposes of Phase II were to (1) develop an assessment system for measuring teacher and pupil behaviors and other factors which could influence each of them and…

Model Transformation for a System of Systems Dependability Safety Case

NASA Technical Reports Server (NTRS)

Murphy, Judy; Driskell, Steve

2011-01-01

The presentation reviews the dependability and safety effort of NASA's Independent Verification and Validation Facility. Topics include: safety engineering process, applications to non-space environment, Phase I overview, process creation, sample SRM artifact, Phase I end result, Phase II model transformation, fault management, and applying Phase II to individual projects.

Early Restoration | NOAA Gulf Spill Restoration

Science.gov Websites

Early Restoration Plan. On April 20, 2011 we reached an agreement with BP to start restoration planning draft plan for the third phase of early restoration in December 2013. We are considering your comments : All Phase III information and documents Phase II Useful Links: Phase II Early Restoration Plan &

Effectiveness of safety belt warning and interlock systems

DOT National Transportation Integrated Search

1973-04-01

Rental cars in Fayetteville, N.C., were equipped with four seat belt and warning systems: (Phase I) detachable shoulder and lap belt, no warning system; (Phase II) detachable shoulder and lap belt, warning system (January 1, 1972 standard); (Phase II...

Recent Advances in Understanding of Kinetic Interplay Between Phase II Metabolism and Efflux Transport.

PubMed

Wang, Shuai; Xing, Huijie; Zhao, Mengjing; Lu, Danyi; Li, Zhijie; Dong, Dong; Wu, Baojian

2016-01-01

Mechanistic understanding of the metabolism-transport interplay assumes great importance in pharmaceutical fields because the knowledge can help to interpret drug/xenobiotic metabolism and disposition studies as well as the drug-drug interactions in vivo. About 10 years ago, it started to recognize that cellular phase II metabolism is strongly influenced by the excretion (efflux transport) of generated metabolites, a kinetic phenomenon termed "phase II metabolism-transport interplay". This interplay is believed to have significant effects on the pharmacokinetics (bioavailability) of drugs/chemicals undergoing phase II metabolism. In this article, we review the studies investigating the phase II metabolism-transport interplay using cell models, perfused rat intestine, and intact rats. The potential confounding factors in exploring such interplay is also summarized. Moreover, the mechanism underlying the phase II metabolism-transport interplay is discussed. Various studies with engineered cells and rodents have demonstrated that there is an interaction (interplay) between phase II enzymes and efflux transporters. This type of interplay mainly refers to the dependence of phase II (conjugative) metabolism on the activities of efflux transporters. In general, inhibiting efflux transporters or decreasing their expression causes the reductions in metabolite excretion, apparent excretion clearance (CLapp) and total metabolism (fmet), as well as an increase in the intracellular level of metabolite (Ci). The deconjugation mediated by hydrolase (acting as a "bridge") is essential for the interplay to play out based on pharmacokinetic modeling/simulations, cell and animal studies. The hydrolases bridge the two processes (i.e., metabolite formation and excretion) and enable the interplay thereof (a bridging effect). Without the bridge, metabolite formation is independent on its downstream process excretion, thus impact of metabolite excretion on its formation is impossible. Deconjugation (mediated by hydrolases) plays an essential role in the conjugation-transport interplay. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

High-Frequency Percussive Ventilation in Patients with Inhalation Injury

DTIC Science & Technology

1989-01-01

inhalation injury. 21). High-frequency ventilation has been shown to be ef- METHODS fective in several clinical and laboratory trials ( 1 -3, 6-8, 17). The...Bear II or Seimens 900C ventilator. In each case the ability to 1 4 Male 43.5 18 Pneumonia maintain normocapnia or an arterial 0, saturation of greater...42.5 1 Group II consists cf the first ten patients who were enrolled 4 1 Female 59 11 Pneumonia in an ongoing prospective study of the use of high

Improving the Ar I and II branching ratio calibration method: Monte Carlo simulations of effects from photon scattering/reflecting in hollow cathodes

NASA Astrophysics Data System (ADS)

Lawler, J. E.; Den Hartog, E. A.

2018-03-01

The Ar I and II branching ratio calibration method is discussed with the goal of improving the technique. This method of establishing a relative radiometric calibration is important in ongoing research to improve atomic transition probabilities for quantitative spectroscopy in astrophysics and other fields. Specific suggestions are presented along with Monte Carlo simulations of wavelength dependent effects from scattering/reflecting of photons in a hollow cathode.

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

PubMed

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

2017-04-01

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

A wandering mind is an unhappy mind.

PubMed

Killingsworth, Matthew A; Gilbert, Daniel T

2010-11-12

We developed a smartphone technology to sample people's ongoing thoughts, feelings, and actions and found (i) that people are thinking about what is not happening almost as often as they are thinking about what is and (ii) found that doing so typically makes them unhappy.

Reflective Cracking of Flexible Pavements Phase I and II Final Recommendations

DOT National Transportation Integrated Search

2008-02-02

This report summarizes all the findings and recommendations from the Phase I and Phase II of the Nevada Department of Transportation (NDOT) study initiated in 2006 to mitigate reflective cracking in hot mix asphalt (HMA) overlays. Based on the analys...

Prostate Cancer Clinical Trials Group: The University of Michigan Site

DTIC Science & Technology

2012-04-01

and fusion-negative strata. UM will be the lead site for this trial with the Univ. of Chicago N01 Phase II consortium as the coordinating center. Ten...sensitive prostate cancer: a University of Chicago Phase II Consortium/Department of Defense Prostate Cancer Clinical Trials Consortium study. JE Ward, T...N01 contract with CTEP (University of Chicago – Early Therapeutics Development with Phase II emphasis group). The Program is committed to creating

The effect of high-, moderate-, and low-fat diets on weight loss and cardiovascular disease risk factors.

PubMed

Fleming, Richard M

2002-01-01

Over 60% of Americans are overweight and a number of popular diets have been advocated, often without evidence, to alleviate this public health hazard. This study was designed to investigate the effects of several diets on weight loss, serum lipids, and other cardiovascular disease risk factors. One hundred men and women followed one of four dietary programs for 1 year: a moderate-fat (MF) program without calorie restriction (28 patients); a low-fat (LF) diet (phase I) (16) ; a MF, calorie-controlled (phase II) diet (38 patients); and a high-fat (HF) diet (18 subjects) [corrected]. Weight, total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides (TG), homocysteine (Ho), and lipoprotein(a) [Lp(a)], were measured every 4th month. The TC/HDL-C ratio was calculated and fibrinogen levels were measured at baseline and after one year. The MF diet resulted in a 2.6% (NS) decrease in weight compared with 18.4% (p=0.045) decrease in patients on phase I, 12.6% (p=0.0085) decrease in patients on phase II, and 13.7% (p=0.025) decrease in those on the HF diet. TC was reduced by 5% (NS) in the MF group, 39.1% (p=0.0005) in the phase I group, and 30.4% (p=0.0001) in the phase II group. HF group had a 4.3% (NS) increase in TC. LDL-C was reduced by 6.1% (NS) on MF, 52.0% (p=0.0001) on phase I, and 38.8% (p=0.0001) on phase II. Patients on HF had a 6.0% (NS) increase in LDL-C. There were nonsignificant reductions in HDL-C in those on MF (-1.5%) and HF (-5.8%). Patients on phase I showed an increase in HDL-C of 9.0% (NS), while those on phase II diet had a 3.6% increase (NS) in HDL-C. TC/HDL-C increased (9.8%) only in patients following the high-fat diets (NS). Patients on MF had a 5.3% (NS) reduction in TC/HDL-C, while those on LF had significant reductions on the phase I ( -45.8%; p=0.0001) diet and phase II diet (-34.7%; p=0.0001). TG levels increased on both the MF (1.0%) and HF (5.5%) diets, although neither was statistically significant. People following the phase I and II diets showed reductions of 37.3% and 36.9%, respectively. Ho levels increased by 9.7% when people followed the MF diet and by 12.4% when they followed the HF diet. Patients following the phase I and phase II diets showed reductions of 13.6% and 14.6%, respectively. Only those following phase II diets showed a tendency toward significant improvement (p=0.061). Lp(a) levels increased by 4.7% following the MF (NS) diet and by 31.0% (NS) on the HF diet. Patients following phase I showed a 7.4% (NS) reduction and a 10.8% reduction (NS) following phase II. Fibrinogen levels increased only in individuals following HF diets (11.9%), while patients following MF (-0.6%), phase I (-11.0%), and phase II (-6.3%) diets showed nonsignificant reductions in fibrinogen. Patients on MF demonstrated nonsignificant reductions in weight, LDL-C, TC, HDL-C, TC/HDL-C ratios, and fibrinogen and nonsignificant increases in TGs, Lp(a), and homocysteine. There was significant weight loss in patients on phase I and II and HF diets after 1 year. Reductions in TC, LDL-C, TGs, and TC/HDL ratios were significant only in patients either following a LF diet or a MF, calorically reduced diet. Only patients following HF diets showed a worsening of each cardiovascular disease risk factor (LDL-C, TG, TC, HDL-C, TC/HDL ratio, Ho, Lp(a), and fibrinogen), despite achieving statistically significant weight loss. Copyright 2002 CHF, Inc.

Research safety vehicle, Phase II. Volume I. Executive summary. Final report jul 75-dec 76

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

Struble, D.

1976-12-01

Volume I summarizes the results of the Minicars Research Safety Vehicle Phase II program, as detailed in Volumes II and III. Phase I identified trends leading to the desired national social goals of the mid-1980's in vehicle crashworthiness, crash avoidance, damageability, pedestrian safety, fuel economy, emissions and cost, and characterized an RSV to satisfy them. In Phase II an RSV prototype was designed, developed and tested to demonstrate the feasibility of meeting these goals simultaneously. Although further refinement is necessary to assure operational validity, in all categories the results meet or exceed the most advanced performance specified by The Presidentialmore » Task Force on Motor Vehicle Goals beyond 1980.« less

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.

Workshop on Radio Transients

NASA Astrophysics Data System (ADS)

Croft, Steve; Gaensler, Bryan

2012-04-01

abstract-type="normal">SummaryWe are entering a new era in the study of variable and transient radio sources. This workshop discussed the instruments and the strategies employed to study those sources, how they are identified and classified, how results from different surveys can be compared, and how radio observations tie in with those at other wavelengths. The emphasis was on learning what common ground there is between the plethora of on-going projects, how methods and code can be shared, and how best practices regarding survey strategy could be adopted. The workshop featured the four topics below. Each topic commenced with a fairly brief introductory talk, which then developed into discussion. By way of preparation, participants had been invited to upload and discuss one slide per topic to a wiki ahead of the workshop. 1. Telescopes, instrumentation and survey strategy. New radio facilities and on-going projects (including upgrades) are both studying the variability of the radio sky, and searching for transients. The discussion first centred on the status of those facilities, and on projects with a time-domain focus, both ongoing and planned, before turning to factors driving choices of instrumentation, such as phased array versus single pixel feeds, the field of view, spatial and time resolution, frequency and bandwidth, depth, area, and cadence of the surveys. 2. Detection, pipelines, and classification. The workshop debated (a) the factors that influence decisions to study variability in the (u,v) plane, in images, or in catalogues, (b) whether, and how much, pipeline code could potentially be shared between one project and another, and which software packages are best for different approaches, (c) how data are stored and later accessed, and (d) how transients and variables are defined and classified. 3. Statistics, interpretation, and synthesis. It then discussed how (i) the choice of facility and strategy and (ii) detection and classification schemes influence what is seen (in terms of types of object and rates) by different surveys, (iii) how results from different surveys could be compared, and (iv) how what we know from existing surveys drives choices (i) and (ii), particularly as regards finding new classes of object. 4. Multiwavelength approaches. The workshop concluded by discussing what information is needed from wavelengths other than radio in order to classify transients and variables adequately and predict their rates as a function of topics (1), (2) and (3). It asked what the constraints are on responding to, and issuing triggers for, follow-up observations, and how that might feed back into considerations for designing our telescopes and surveys.

Clinical validity of cerebrospinal fluid Aβ42, tau, and phospho-tau as biomarkers for Alzheimer's disease in the context of a structured 5-phase development framework.

PubMed

Mattsson, Niklas; Lönneborg, Anders; Boccardi, Marina; Blennow, Kaj; Hansson, Oskar

2017-04-01

Novel diagnostic criteria for Alzheimer's disease (AD) incorporate biomarkers, but their maturity for implementation in clinical practice at the prodromal stage (mild cognitive impairment [MCI]) is unclear. Here, we evaluate cerebrospinal fluid (CSF) β-amyloid 42 (Aβ42), total tau, and phosphorylated tau in the light of a 5-phase framework for biomarker development. Ample evidence is available for phase 1 (identifying useful leads) and phase 2 (assessing the accuracy for AD dementia versus controls) for CSF biomarkers. Phase 3 (utility in MCI) is partially achieved. In cohorts with long follow-up time, CSF Aβ42, total tau, and phosphorylated tau have high diagnostic accuracy for MCI due to AD. Phase 4 (performance in real world) is ongoing, and phase 5 studies (quantify impact and costs) are to come. Our results highlight priorities to pursue and to enable the proper use of CSF biomarkers in the clinic. Priorities are to reduce measurement variability by introduction of fully automated assay systems; to increase diagnostic specificity toward non-AD neurocognitive diseases at the MCI stage; and to clarify the role of CSF biomarkers versus other biomarker modalities in clinical practice and in design of clinical trials. These efforts are currently ongoing. Copyright © 2016 Elsevier Inc. All rights reserved.

Local analogues of high-redshift star-forming galaxies: integral field spectroscopy of green peas

NASA Astrophysics Data System (ADS)

Lofthouse, E. K.; Houghton, R. C. W.; Kaviraj, S.

2017-10-01

We use integral field spectroscopy, from the SWIFT and PALM3K instruments, to perform a spatially resolved spectroscopic analysis of four nearby highly star-forming 'green pea' (GP) galaxies, that are likely analogues of high-redshift star-forming systems. By studying emission-line maps in H α, [N II] λλ6548,6584 and [S II] λλ6716,6731, we explore the kinematic morphology of these systems and constrain properties such as gas-phase metallicities, electron densities and gas-ionization mechanisms. Two of our GPs are rotationally supported while the others are dispersion-dominated systems. The rotationally supported galaxies both show evidence for recent or ongoing mergers. However, given that these systems have intact discs, these interactions are likely to have low-mass ratios (I.e. minor mergers), suggesting that the minor-merger process may be partly responsible for the high star formation rates seen in these GPs. Nevertheless, the fact that the other two GPs appear morphologically undisturbed suggests that mergers (including minor mergers) are not necessary for driving the high star formation rates in such galaxies. We show that the GPs are metal-poor systems (25-40 per cent of solar) and that the gas ionization is not driven by active galactic nuclei (AGN) in any of our systems, indicating that the AGN activity is not coeval with star formation in these starbursting galaxies.

A two-stage patient enrichment adaptive design in phase II oncology trials.

PubMed

Song, James X

2014-01-01

Illustrated is the use of a patient enrichment adaptive design in a randomized phase II trial which allows the evaluation of treatment benefits by the biomarker expression level and makes interim adjustment according to the pre-specified rules. The design was applied to an actual phase II metastatic hepatocellular carcinoma (HCC) trial in which progression-free survival (PFS) in two biomarker-defined populations is evaluated at both interim and final analyses. As an extension, a short-term biomarker is used to predict the long-term PFS in a Bayesian model in order to improve the precision of hazard ratio (HR) estimate at the interim analysis. The characteristics of the extended design are examined in a number of scenarios via simulations. The recommended adaptive design is shown to be useful in a phase II setting. When a short-term maker which correlates with the long-term PFS is available, the design can be applied in smaller early phase trials in which PFS requires longer follow-up. In summary, the adaptive design offers flexibility in randomized phase II patient enrichment trials and should be considered in an overall personalized healthcare (PHC) strategy. Copyright © 2013 Elsevier Inc. All rights reserved.

U10 : Trusted Truck(R) II (phase B).

DOT National Transportation Integrated Search

2009-01-01

Phase B of the Trusted Truck II project built on the system developed in Phase A (or Year 1). For the implementation portion of the project, systems were added to the trailer to provide additional diagnostic trailer data that can be sent to the TTM...

Movement Analysis Applied to the Basketball Jump Shot--Part II.

ERIC Educational Resources Information Center

Martin, Thomas P.

1981-01-01

The jump shot is one of the most important shots in the game of basketball. The movement analysis of the jump shot designates four phases: (1) preparatory position; (2) movement phase I (crouch); (3) movement phase II (jump); and (4) follow-through. (JN)

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

The evolution of γ-Mg17Al12 intermetallic compound during accumulative back extrusion and subsequent ageing treatment

NASA Astrophysics Data System (ADS)

Maghsoudi, M. H.; Zarei-Hanzaki, A.; Abedi, H. R.; Shamsolhodaei, A.

2015-11-01

Accumulative back extrusion (ABE) processing, as a novel severe plastic deformation (SPD) method, has been recently justified to be capable of modifying the microstructural characteristics of alloys. In line to its ongoing researches, the present work has been planned to study the evolution of γ-Mg17Al12 intermetallic phase during ABE and subsequent ageing treatment in a high Al-bearing Mg-Al-Zn alloy. The behaviour of γ intermetallic has been systematically examined as following points of view: (i) strain-temperature-dependent morphology changes, (ii) strain-induced dissolution, and (iii) re-ageing behaviour as a function of time and temperature. Aiming to analyse the morphology of eutectic γ compound with respect to the strain and temperature, 2D projections of effective diameter, shape factor and globularity have been made in strain/temperature graphs. The processing conditions (strain and temperature) corresponding to the desired and undesired morphologies are introduced and microstructurally explained through underlying plasticity mechanisms, i.e., 'necking-thinning-particle separation' and 'brittle fragmentation.' The former mechanism is suggested to be in relation with partial strain-induced dissolution of eutectic γ phase, leading to generation of a supersaturated solid solution. This has resulted to the observation of 'off-stoichiometry' phenomena in Mg17Al12 phase and has been justified through dislocation-assisted deformation mechanism at elevated temperature. Surprisingly, a unique re-ageing behaviour has been found for the obtained solid solutions, where a modified kinetics and morphology of γ phase precipitation were characterized. The altered precipitation behaviour is attributed to the specific defect structure achieved by SPD acting as fast diffusion channel for Al solutes.

A Web-Based Intervention to Reduce Distress After Prostate Cancer Treatment: Development and Feasibility of the Getting Down to Coping Program in Two Different Clinical Settings.

PubMed

Cockle-Hearne, Jane; Barnett, Deborah; Hicks, James; Simpson, Mhairi; White, Isabel; Faithfull, Sara

2018-04-30

Distress after prostate cancer treatment is a substantial burden for up to one-third of men diagnosed. Physical and emotional symptoms and health service use can intensify, yet men are reticent to accept support. To provide accessible support that can be cost effectively integrated into care pathways, we developed a unique, Web-based, self-guided, cognitive-behavior program incorporating filmed and interactive peer support. To assess feasibility of the intervention among men experiencing distress after prostate cancer treatment. Demand, acceptability, change in distress and self-efficacy, and challenges for implementation in clinical practice were measured. A pre-post, within-participant comparison, mixed-methods research design was followed. Phase I and II were conducted in primary care psychological service and secondary care cancer service, respectively. Men received clinician-generated postal invitations: phase I, 432 men diagnosed <5 years; phase II, 606 men diagnosed <3.5 years. Consent was Web-based. Men with mild and moderate distress were enrolled. Web-based assessment included demographic, disease, treatment characteristics; distress (General Health Questionnaire-28); depression (Patient Health Questionnaire-9); anxiety (General Anxiety Disorder Scale-7); self-efficacy (Self-Efficacy for Symptom Control Inventory); satisfaction (author-generated, Likert-type questionnaire). Uptake and adherence were assessed with reference to the persuasive systems design model. Telephone interviews explored participant experience (phase II, n=10); interviews with health care professionals (n=3) explored implementation issues. A total of 135 men consented (phase I, 61/432, 14.1%; phase II, 74/606, 12.2%); from 96 eligible men screened for distress, 32% (30/96) entered the intervention (phase I, n=10; phase II, n=20). Twenty-four completed the Web-based program and assessments (phase I, n=8; phase II, n=16). Adherence for phase I and II was module completion rate 63% (mean 2.5, SD 1.9) versus 92% (mean 3.7, SD 1.0); rate of completing cognitive behavior therapy exercises 77% (mean 16.1, SD 6.2) versus 88% (mean 18.6, SD 3.9). Chat room activity occurred among 63% (5/8) and 75% (12/16) of men, respectively. In phase I, 75% (6/8) of men viewed all the films; in phase II, the total number of unique views weekly was 16, 11, 11, and 10, respectively. The phase II mood diary was completed by 100% (16/16) of men. Satisfaction was high for the program and films. Limited efficacy testing indicated improvement in distress baseline to post intervention: phase I, P=.03, r=-.55; phase II, P=.001, r=-.59. Self-efficacy improved for coping P=.02, r=-.41. Service assessment confirmed ease of assimilation into clinical practice and clarified health care practitioner roles. The Web-based program is acceptable and innovative in clinical practice. It was endorsed by patients and has potential to positively impact the experience of men with distress after prostate cancer treatment. It can potentially be delivered in a stepped model of psychological support in primary or secondary care. Feasibility evidence is compelling, supporting further evaluative research to determine clinical and cost effectiveness. ©Jane Cockle-Hearne, Deborah Barnett, James Hicks, Mhairi Simpson, Isabel White, Sara Faithfull. Originally published in JMIR Cancer (http://cancer.jmir.org), 30.04.2018.

A Web-Based Intervention to Reduce Distress After Prostate Cancer Treatment: Development and Feasibility of the Getting Down to Coping Program in Two Different Clinical Settings

PubMed Central

Barnett, Deborah; Hicks, James; Simpson, Mhairi; White, Isabel; Faithfull, Sara

2018-01-01

Background Distress after prostate cancer treatment is a substantial burden for up to one-third of men diagnosed. Physical and emotional symptoms and health service use can intensify, yet men are reticent to accept support. To provide accessible support that can be cost effectively integrated into care pathways, we developed a unique, Web-based, self-guided, cognitive-behavior program incorporating filmed and interactive peer support. Objective To assess feasibility of the intervention among men experiencing distress after prostate cancer treatment. Demand, acceptability, change in distress and self-efficacy, and challenges for implementation in clinical practice were measured. Methods A pre-post, within-participant comparison, mixed-methods research design was followed. Phase I and II were conducted in primary care psychological service and secondary care cancer service, respectively. Men received clinician-generated postal invitations: phase I, 432 men diagnosed <5 years; phase II, 606 men diagnosed <3.5 years. Consent was Web-based. Men with mild and moderate distress were enrolled. Web-based assessment included demographic, disease, treatment characteristics; distress (General Health Questionnaire-28); depression (Patient Health Questionnaire-9); anxiety (General Anxiety Disorder Scale-7); self-efficacy (Self-Efficacy for Symptom Control Inventory); satisfaction (author-generated, Likert-type questionnaire). Uptake and adherence were assessed with reference to the persuasive systems design model. Telephone interviews explored participant experience (phase II, n=10); interviews with health care professionals (n=3) explored implementation issues. Results A total of 135 men consented (phase I, 61/432, 14.1%; phase II, 74/606, 12.2%); from 96 eligible men screened for distress, 32% (30/96) entered the intervention (phase I, n=10; phase II, n=20). Twenty-four completed the Web-based program and assessments (phase I, n=8; phase II, n=16). Adherence for phase I and II was module completion rate 63% (mean 2.5, SD 1.9) versus 92% (mean 3.7, SD 1.0); rate of completing cognitive behavior therapy exercises 77% (mean 16.1, SD 6.2) versus 88% (mean 18.6, SD 3.9). Chat room activity occurred among 63% (5/8) and 75% (12/16) of men, respectively. In phase I, 75% (6/8) of men viewed all the films; in phase II, the total number of unique views weekly was 16, 11, 11, and 10, respectively. The phase II mood diary was completed by 100% (16/16) of men. Satisfaction was high for the program and films. Limited efficacy testing indicated improvement in distress baseline to post intervention: phase I, P=.03, r=−.55; phase II, P=.001, r=−.59. Self-efficacy improved for coping P=.02, r=−.41. Service assessment confirmed ease of assimilation into clinical practice and clarified health care practitioner roles. Conclusions The Web-based program is acceptable and innovative in clinical practice. It was endorsed by patients and has potential to positively impact the experience of men with distress after prostate cancer treatment. It can potentially be delivered in a stepped model of psychological support in primary or secondary care. Feasibility evidence is compelling, supporting further evaluative research to determine clinical and cost effectiveness. PMID:29712628

ACOT Classroom Networks: Today and Tomorrow. ACOT Report #5.

ERIC Educational Resources Information Center

Knapp, Linda

The Apple Classrooms of Tomorrow (ACOT) research project provides classroom sites with equipment, ongoing support, and training, enabling educators to discover the potential of networked learning environments. ACOT networks link together technology from Apple IIe computers and Image Writer printers, to Macintosh II systems, synthesizers, laserdisc…

42 CFR 2.12 - Applicability.

Code of Federal Regulations, 2014 CFR

2014-10-01

... ALCOHOL AND DRUG ABUSE PATIENT RECORDS General Provisions § 2.12 Applicability. (a) General—(1... identification by another person; and (ii) Is drug abuse information obtained by a federally assisted drug abuse... assisted alcohol or drug abuse program after that date as part of an ongoing treatment episode which...

42 CFR 2.12 - Applicability.

Code of Federal Regulations, 2012 CFR

2012-10-01

... ALCOHOL AND DRUG ABUSE PATIENT RECORDS General Provisions § 2.12 Applicability. (a) General—(1... identification by another person; and (ii) Is drug abuse information obtained by a federally assisted drug abuse... assisted alcohol or drug abuse program after that date as part of an ongoing treatment episode which...

42 CFR 2.12 - Applicability.

Code of Federal Regulations, 2011 CFR

2011-10-01

... ALCOHOL AND DRUG ABUSE PATIENT RECORDS General Provisions § 2.12 Applicability. (a) General—(1... identification by another person; and (ii) Is drug abuse information obtained by a federally assisted drug abuse... assisted alcohol or drug abuse program after that date as part of an ongoing treatment episode which...

42 CFR 2.12 - Applicability.

Code of Federal Regulations, 2010 CFR

2010-10-01

... ALCOHOL AND DRUG ABUSE PATIENT RECORDS General Provisions § 2.12 Applicability. (a) General—(1... identification by another person; and (ii) Is drug abuse information obtained by a federally assisted drug abuse... assisted alcohol or drug abuse program after that date as part of an ongoing treatment episode which...

42 CFR 2.12 - Applicability.

Code of Federal Regulations, 2013 CFR

2013-10-01

... ALCOHOL AND DRUG ABUSE PATIENT RECORDS General Provisions § 2.12 Applicability. (a) General—(1... identification by another person; and (ii) Is drug abuse information obtained by a federally assisted drug abuse... assisted alcohol or drug abuse program after that date as part of an ongoing treatment episode which...

Sulforaphane-stimulated phase II enzyme induction inhibits cytokine production by airway epithelial cells stimulated with diesel extract.

PubMed

Ritz, Stacey A; Wan, Junxiang; Diaz-Sanchez, David

2007-01-01

Airborne particulate pollutants, such as diesel exhaust particles, are thought to exacerbate lung and cardiovascular diseases through induction of oxidative stress. Sulforaphane, derived from cruciferous vegetables, is the most potent known inducer of phase II enzymes involved in the detoxification of xenobiotics. We postulated that sulforaphane may be able to ameliorate the adverse effects of pollutants by upregulating expression of endogenous antioxidant enzymes. Stimulation of bronchial epithelial cells with the chemical constituents of diesel particles result in the production of proinflammatory cytokines. We first demonstrated a role for phase II enzymes in regulating diesel effects by transfecting the airway epithelial cell line (BEAS-2B) with the sentinel phase II enzyme NAD(P)H: quinine oxidoreductase 1 (NQO1). IL-8 production in response to diesel extract was significantly reduced in these compared with untransfected cells. We then examined whether sulforaphane would stimulate phase II induction and whether this would thereby ablate the effect of diesel extracts on cytokine production. We verified that sulforaphane significantly augmented expression of the phase II enzyme genes GSTM1 and NQO1 and confirmed that sulforaphane treatment increased glutathione S-transferase activity in epithelial cells without inducing cell death or apoptosis. Sulforaphane pretreatment inhibited IL-8 production by BEAS-2B cells upon stimulation with diesel extract. Similarly, whereas diesel extract stimulated production of IL-8, granulocyte-macrophage colony-stimulating factor, and IL-1beta from primary human bronchial epithelial cells, sulforaphane pretreatment inhibited diesel-induced production of all of these cytokines. Our studies show that sulforaphane can mitigate the effect of diesel in respiratory epithelial cells and demonstrate the chemopreventative potential of phase II enzyme enhancement.

Installation Restoration Program. Remedial Investigation Report. Minnesota Air National Guard Base Duluth International Airport, Duluth, Minnesota. Volume 5

DTIC Science & Technology

1990-01-01

1-20 1-6 Sites Defined and Ranked During IRP Phase I Study. 1-29 1-7 Aerial Photograph of Site 2, April 1988. 1-32 1-8 Site 2 Sampling Locations...Utilized During Phase II Investigations. 1-35 1-9 Aerial Photograph of Site 3, April 1988. 1-38 1-10 Site 3 Sampling Locations Utilized During Phase II...Investigations. 1-47 1-11 Aerial Photograph of Site 4, April 1988. 1-54 1-12 Site 4 Sampling Locations Utilized During Phase II Investigations. 1-57 1-13

Piper betle Induced Cytoprotective Genes and Proteins via the Nrf2/ARE Pathway in Aging Mice.

PubMed

Aliahmat, Nor Syahida; Abdul Sani, Nur Fathiah; Wan Hasan, Wan Nuraini; Makpol, Suzana; Wan Ngah, Wan Zurinah; Mohd Yusof, Yasmin Anum

2016-01-01

The objective of this study was to elucidate the underlying antioxidant mechanism of aqueous extract of Piper betle (PB) in aging rats. The nuclear factor erythroid 2-related factor 2 (Nrf2)/ARE pathway involving phase II detoxifying and antioxidant enzymes plays an important role in the antioxidant system by reducing electrophiles and reactive oxygen species through induction of phase II enzymes and proteins. Genes and proteins of phase II detoxifying antioxidant enzymes were analyzed by QuantiGenePlex 2.0 Assay and Western blot analysis. PB significantly induced genes and proteins of phase II and antioxidant enzymes, NAD(P)H quinone oxidoreductase 1, and catalase in aging mice (p < 0.05). The expression of these enzymes were stimulated via translocation of Nrf2 into the nucleus, indicating the involvement of ARE, a cis-acting motif located in the promoter region of nearly all phase II genes. PB was testified for the first time to induce cytoprotective genes through the Nrf2/ARE signaling pathway, thus unraveling the antioxidant mechanism of PB during the aging process. © 2016 S. Karger AG, Basel.

Can blood and semen presepsin levels in males predict pregnancy in couples undergoing intra-cytoplasmic sperm injection?

PubMed

Ovayolu, Ali; Arslanbuğa, Cansev Yilmaz; Gun, Ismet; Devranoglu, Belgin; Ozdemir, Arman; Cakar, Sule Eren

2016-01-01

To determine whether semen and plasma presepsin values measured in men with normozoospermia and oligoasthenospermia undergoing invitro-fertilization would be helpful in predicting ongoing pregnancy and live birth. Group-I was defined as patients who had pregnancy after treatment and Group-II comprised those with no pregnancy. Semen and blood presepsin values were subsequently compared between the groups. Parametric comparisons were performed using Student's t-test, and non-parametric comparisons were conducted using the Mann-Whitney U test. There were 42 patients in Group-I and 72 in Group-II. In the context of successful pregnancy and live birth, semen presepsin values were statistically significantly higher in Group-I than in Group-II (p= 0.004 and p= 0.037, respectively). The most appropriate semen presepsin cut-off value for predicting both ongoing pregnancy and live birth was calculated as 199 pg/mL. Accordingly, their sensitivity was 64.5% to 59.3%, their specificity was 57.0% to 54.2%, and their positive predictive value was 37.0% to 29.6%, respectively; their negative predictive value was 80.4% in both instances. Semen presepsin values could be a new marker that may enable the prediction of successful pregnancy and/or live birth. Its negative predictive values are especially high.

Summary - National Dissemination and the Five Target States, Part 3, Final Report for Phase II--Dissemination, Rural Shared Services.

ERIC Educational Resources Information Center

Northern Montana Coll., Havre.

The dissemination phase (Phase II) of the Rural Shared Services Project is reported in this document. Efforts of the dissemination phase were concentrated in 5 target states: Vermont, Georgia, Wyoming, Montana, and New Mexico; national dissemination was limited to attendance at national conferences, the U. S. Office of Education PREP materials for…

Site preference of alloying elements in DO22-Ni3V phase: Phase-field and first-principles study

NASA Astrophysics Data System (ADS)

Zhang, Ding-Ni; Shangguan, Qian-Qian; Liu, Fu; Zhang, Ming-Yi

2015-07-01

Site preference of alloying elements in DO22-Ni3V phase was investigated using phase-field and first-principles method. The concentrations of alloying elements on sublattices of DO22-Ni3V phase were quantitatively studied using phase-field model based on microscopic diffusion equations. The phase-field computation results demonstrate that the concentration differences of alloying elements on the NiI and NiII site are attributed to the coordination environment difference. Host atoms Ni and substitutional ternary additions Al prefer to occupy NiI site. Antisite atoms V show site preference on the NiII site. Further reason of site preference of alloying elements on the two different Ni sites were studied using first-principles method to calculate the electronic structure of DO22-Ni3V phase. Calculation of density of states, orbitals population and charge population of the optimized Ni3V structure found that the electronic structures of NiI and NiII sites are different. Electronic structure difference, which is caused by coordination environment difference, is the essential reason for site selectivity behaviors of alloying elements on NiI and NiII sites.

Bibliographic Automation of Large Library Operations Using a Time-Sharing System: Phase I. Final Report.

ERIC Educational Resources Information Center

Epstein, A. H.; And Others

The first phase of an ongoing library automation project at Stanford University is described. Project BALLOTS (Bibliographic Automation of Large Library Operations Using a Time-Sharing System) seeks to automate the acquisition and cataloging functions of a large library using an on-line time-sharing computer. The main objectives are to control…

Preconditions for Post-Employment Learning: Preliminary Results from Ongoing Research

ERIC Educational Resources Information Center

Salter, Linda

2011-01-01

This article describes the first phase of a two-phase, mixed-method study. The study, now in progress, explores how and to what extent willingness to engage in learning in mature adulthood is influenced by prior experiences and specific individual personality variables, such as perceived locus of control and degree of self-efficacy. Study…

Computer Simulations of Polytetrafluoroethylene in the Solid State

NASA Astrophysics Data System (ADS)

Holt, D. B.; Farmer, B. L.; Eby, R. K.; Macturk, K. S.

1996-03-01

Force field parameters (Set I) for fluoropolymers were previously derived from MOPAC AM1 semiempirical data on model molecules. A second set (Set II) was derived from the AM1 results augmented by ab initio calculations. Both sets yield reasonable helical and phase II packing structures for polytetrafluoroethylene (PTFE) chains. However, Set I and Set II differ in the strength of van der Waals interactions, with Set II having deeper potential wells (order of magnitude). To differentiate which parameter set provides a better description of PTFE behavior, molecular dynamics simulations have been performed with Biosym Discover on clusters of PTFE chains which begin in a phase II packing environment. Added to the model are artificial constraints which allow the simulation of thermal expansion without having to define periodic boundary conditions for each specific temperature of interest. The preliminary dynamics simulations indicate that the intra- and intermolecular interactions provided by Set I are too weak. The degree of helical disorder and chain motion are high even at temperatures well below the phase II-phase IV transition temperature (19 C). Set II appears to yield a better description of PTFE in the solid state.

Design, analysis, and test verification of advanced encapsulation systems

NASA Technical Reports Server (NTRS)

Mardesich, N.; Minning, C.

1982-01-01

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

Technology Demonstration of the Zero Emissions Chromium Electroplating System

DTIC Science & Technology

2008-02-01

Phase I trivalent chromium results ................................................................... 23 18 Phase II total chromium in PRD fluid results...0 xa B D F H J L Sam pies Figure 16. Phase II iron results. ERDC/CERL TR-05-35, Vol. 1 23 Trivalent Chromium Phase I Analysis for Phase I was...with the samples. Each sample was analyzed twice, and an average was computed. Figure 17 shows the results. ANAD has specified that Trivalent Chromium

Automated Methodologies for the Design of Flow Diagrams for Development and Maintenance Activities

NASA Astrophysics Data System (ADS)

Shivanand M., Handigund; Shweta, Bhat

The Software Requirements Specification (SRS) of the organization is a text document prepared by strategic management incorporating the requirements of the organization. These requirements of ongoing business/ project development process involve the software tools, the hardware devices, the manual procedures, the application programs and the communication commands. These components are appropriately ordered for achieving the mission of the concerned process both in the project development and the ongoing business processes, in different flow diagrams viz. activity chart, workflow diagram, activity diagram, component diagram and deployment diagram. This paper proposes two generic, automatic methodologies for the design of various flow diagrams of (i) project development activities, (ii) ongoing business process. The methodologies also resolve the ensuing deadlocks in the flow diagrams and determine the critical paths for the activity chart. Though both methodologies are independent, each complements other in authenticating its correctness and completeness.

Laboratory modeling of energy dissipation in broken-back culverts - phase II.

DOT National Transportation Integrated Search

2011-05-01

This report represents Phase II of broken-back culverts with a drop of 6 feet. The first phase of this research was performed for a drop of 24 feet. This research investigates the reduction in scour downstream of a broken-back culvert by forming a hy...

DEVELOPMENT OF A SCALABLE, LOW-COST, ULTRANANOCRYSTALLINE DIAMOND ELECTROCHEMICAL PROCESS FOR THE DESTRUCTION OF CONTAMINANTS OF EMERGING CONCERN (CECS) - PHASE II

EPA Science Inventory

This Small Business Innovation Research (SBIR) Phase II project will employ the large scale; highly reliable boron-doped ultrananocrystalline diamond (BD-UNCD®) electrodes developed during Phase I project to build and test Electrochemical Anodic Oxidation process (EAOP)...

78 FR 18305 - Notice of Request for Extension of a Currently Approved Information Collection

Federal Register 2010, 2011, 2012, 2013, 2014

2013-03-26

... Identity Verification (PIV) Request for Credential, the USDA Homeland Security Presidential Directive 12... consists of two phases of implementation: Personal Identity Verification phase I (PIV I) and Personal Identity Verification phase II (PIV II). The information requested must be provided by Federal employees...

A two-step spin crossover mononuclear iron(II) complex with a [HS-LS-LS] intermediate phase.

PubMed

Bonnet, Sylvestre; Siegler, Maxime A; Costa, José Sánchez; Molnár, Gábor; Bousseksou, Azzedine; Spek, Anthony L; Gamez, Patrick; Reedijk, Jan

2008-11-21

The two-step spin crossover of a new mononuclear iron(ii) complex is studied by magnetic, crystallographic and calorimetric methods revealing two successive first-order phase transitions and an ordered intermediate phase built by the repetition of the unprecedented [HS-LS-LS] motif.

The effectiveness and safety of traffic and non-traffic related messages presented on changeable message signs : phase II.

DOT National Transportation Integrated Search

2008-08-01

In Phase II of this investigation, we used a fully interactive PC-based STISIM driving simulator, to conduct two : experiments which were similar to experiments in Phase I. The participants were 120 licensed drivers from three : age groups18-24, 3...

Tipster Text Phase 2 Architecture Design

DTIC Science & Technology

1996-06-19

TIPSTER Text Phase II Architecture Design Version 2.1p 19 June 1996 Ralph Grishman New York University grishman @cs.nyu.edu and the TIPSTER...1996 2. REPORT TYPE 3. DATES COVERED 00-00-1996 to 00-00-1996 4. TITLE AND SUBTITLE TIPSTER Text Phase II Architecture Design 5a. CONTRACT

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

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.

Asiago spectroscopic classification of 5 ASASSN SNe

NASA Astrophysics Data System (ADS)

Tomasella, L.; Benetti, S.; Cappellaro, E.; Turatto, M.

2018-04-01

The Asiago Transient Classification Program (Tomasella et al. 2014, AN, 335, 841) reports the spectroscopic classification of ASASSN-18ii,ASASSN-18it, ASASSN-18iv, ASASN-18iw, ASASSN-18iu discovered during the ongoing All Sky Automated Survey for SuperNovae (ASAS-SN, Shappee et al. 2014) (Atel #11178).

75 FR 38579 - Self-Regulatory Organizations; National Securities Clearing Corporation; Notice of Filing of...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-07-02

... To Enhance the Process for Transfers Through the Automated Customer Account Transfer Service June 25... NSCC's process for transfers through the Automated Customer Account Transfer Service (``ACATS''). II... services and to effect customer account transfers within specified time frames. \\4\\ CNS is an ongoing...

Conceptual Assessment Tool for Advanced Undergraduate Electrodynamics

ERIC Educational Resources Information Center

Baily, Charles; Ryan, Qing X.; Astolfi, Cecilia; Pollock, Steven J.

2017-01-01

As part of ongoing investigations into student learning in advanced undergraduate courses, we have developed a conceptual assessment tool for upper-division electrodynamics (E&M II): the Colorado UppeR-division ElectrodyNamics Test (CURrENT). This is a free response, postinstruction diagnostic with 6 multipart questions, an optional 3-question…

Overview of the DARPA/AFRL/NASA Smart Wing Phase II program

NASA Astrophysics Data System (ADS)

Kudva, Jayanth N.; Sanders, Brian P.; Pinkerton-Florance, Jennifer L.; Garcia, Ephrahim

2001-06-01

The DARPA/AFRL/NASA Smart Wing program, conducted by a team led by Northrop Grumman Corporation (NGC) under the DARPA Smart Materials and Structures initiative, addresses the development of smart technologies and demonstration of relevant concepts to improve the aerodynamic performance of military aircraft. This paper presents an overview of the smart wing program. The program is divided into two phases. Under Phase 1, (1995 - 1999) the NGC team developed adaptive wing structures with integrated actuation mechanisms to replace standard hinged control surfaces and provide variable, optimal aerodynamic shapes for a variety of flight regimes. Two half-span 16% scale wind tunnel models, representative of an advanced military aircraft wing, one with conventional control surfaces and the other with shape memory alloy (SMA) actuated smart control surfaces, were fabricated and tested in the NASA Langley Research Center (LaRC) Transonic Dynamics Tunnel (TDT) wind tunnel during two series of tests, conducted in May 1996 and June 1998, respectively. Details of the Phase 1 effort are documented in several papers. The on-going Phase 2 effort discussed here was started in January 1997 and includes several significant improvements over Phase 1: 1) a much larger, full-span model; 2) both leading edge (LE) and trailing edge (TE) smart control surfaces; 3) high-band width actuation systems; and 4) wind tunnel tests at transonic Mach numbers and high dynamic pressures (up to 300 psf.) representative of operational flight regimes. Phase 2 includes two wind tunnel tests, both at the NASA LaRC TDT - the first one was completed in March 2000 and the second (and final) test is scheduled for April 2001. The first test-demonstrated roll-effectiveness over a wide range of Mach numbers achieved using a combination of hingeless, smoothly contoured, SMA actuated, LE and TE control surfaces. The second test addresses the development and demonstration of high bandwidth actuation. An overview of the Phase 2 effort is presented here; detailed discussions of the wind tunnel testing, model design and fabrication, and actuation system development are given in companion papers.

The functional performance of the Argus II retinal prosthesis

PubMed Central

Stronks, H Christiaan; Dagnelie, Gislin

2014-01-01

Summary Visual prostheses are devices to treat profound vision loss by stimulating secondary nerve cells anywhere along the visual pathway, typically with electrical pulses. The Argus® II implant, developed by Second Sight Medical Products (SSMP, Sylmar, CA, USA), targets the retina and features 60 electrodes that electrically stimulate the surviving retinal neurons. Of the approximately 20 research groups that are actively developing visual prostheses, SSMP has the longest track record. The Argus II was the first visual prosthesis to become commercially available: It received the CE mark in Europe in 2011 and FDA approval was granted in early 2013 for humanitarian use in the USA. Meanwhile, the Argus II safety/benefit study has been extended for research purposes, and is ongoing. In this review we will discuss the performance of the Argus II in restoring sight to the blind, and we will shed light on its expected developments in the coming years. PMID:24308734

Integration, acceptance testing, and clinical operation of the Medical Information, Communication and Archive System, phase II.

PubMed

Smith, E M; Wandtke, J; Robinson, A

1999-05-01

The Medical Information, Communication and Archive System (MICAS) is a multivendor incremental approach to picture archiving and communications system (PACS). It is a multimodality integrated image management system that is seamlessly integrated with the radiology information system (RIS). Phase II enhancements of MICAS include a permanent archive, automated workflow, study caches, Microsoft (Redmond, WA) Windows NT diagnostic workstations with all components adhering to Digital Information Communications in Medicine (DICOM) standards. MICAS is designed as an enterprise-wide PACS to provide images and reports throughout the Strong Health healthcare network. Phase II includes the addition of a Cemax-Icon (Fremont, CA) archive, PACS broker (Mitra, Waterloo, Canada), an interface (IDX PACSlink, Burlington, VT) to the RIS (IDXrad) plus the conversion of the UNIX-based redundant array of inexpensive disks (RAID) 5 temporary archives in phase I to NT-based RAID 0 DICOM modality-specific study caches (ImageLabs, Bedford, MA). The phase I acquisition engines and workflow management software was uninstalled and the Cemax archive manager (AM) assumed these functions. The existing ImageLabs UNIX-based viewing software was enhanced and converted to an NT-based DICOM viewer. Installation of phase II hardware and software and integration with existing components began in July 1998. Phase II of MICAS demonstrates that a multivendor open-system incremental approach to PACS is feasible, cost-effective, and has significant advantages over a single-vendor implementation.

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.

Geraniol modulates tongue and hepatic phase I and phase II conjugation activities and may contribute directly to the chemopreventive activity against experimental oral carcinogenesis.

PubMed

Madankumar, Arumugam; Jayakumar, Subramaniyan; Gokuladhas, Krishnan; Rajan, Balan; Raghunandhakumar, Subramanian; Asokkumar, Selvamani; Devaki, Thiruvengadam

2013-04-05

Xenobiotic metabolizing enzymes are chief determinants in both the susceptibility to mutagenic effect of chemical carcinogens and in the response of tumors to chemotherapy. The present study was aimed to analyze the effect of geraniol administration on the activity of phase I and phase II carcinogen metabolizing enzymes through the nuclear factor erythroid 2-related factor-2 (Nrf2) activation against 4-niroquinoline-1-oxide (4NQO) induced oral carcinogenesis. The well-known chemical carcinogen 4NQO (50 ppm) was used to induce oral carcinogenesis through drinking water for 4, 12, and 20 weeks. The degree of cancer progression at each stage was confirmed by histological examination. At the end of the experimental period, 100% tumor formation was observed in the oral cavity of 4NQO induced animals with significant (P<0.05) alteration in the status of tumor markers, tongue and liver phase I and phase II drug metabolizing enzymes indicating progression of disease. Oral administration of geraniol at the dose of 200 mg/kg b.wt., thrice a week to 4NQO induced animals was able to inhibit tumor formation and thereby delayed the progression of oral carcinogenesis by modulating tongue and liver phase I and phase II drug metabolizing enzymes, as substantiated further by the histological and transmission electron microscopic studies. Our results demonstrate that geraniol exerts its chemopreventive potential by altering activities of phases I and II drug metabolizing enzymes to achieve minimum bioactivation of carcinogen and maximum detoxification. Copyright © 2013 Elsevier B.V. All rights reserved.

Polymorphism of paracetamol: relative stabilities of the monoclinic and orthorhombic phases inferred from topological pressure-temperature and temperature-volume phase diagrams.

PubMed

Espeau, Philippe; Céolin, René; Tamarit, Josep-Lluis; Perrin, Marc-Antoine; Gauchi, Jean-Pierre; Leveiller, Franck

2005-03-01

The thermodynamic relationships between the two known polymorphs of paracetamol have been investigated, and the subsequent pressure-temperature and temperature-volume phase diagrams were constructed using data from crystallographic and calorimetric measurements as a function of the temperature. Irrespective of temperature, monoclinic Form I and orthorhombic Form II are stable phases at ordinary and high pressures, respectively. The I and II phase regions in the pressure-temperature diagram are bordered by the I-II equilibrium curve, for which a negative slope (dp/dT approximately -0.3 MPa x K(-1)) was determined although it was not observed experimentally. This curve goes through the I-II-liquid triple point whose coordinates (p approximately 234 MPa, T approximately 505 K) correspond to the crossing point of the melting curves, for which dp/dT values of +3.75 MPa x K(-1) (I) and +3.14 MPa x K(-1) (II) were calculated from enthalpy and volume changes upon fusion. More generally, this case exemplifies how the stability hierarchy of polymorphs may be inferred from the difference in their sublimation curves, as topologically positioned with respect to each other, using the phase rule and simple inferences resorting to Gibbs equilibrium thermodynamics. Copyright 2004 Wiley-Liss, Inc. and the American Pharmacists Association.

Imaging Depression in Adults with ASD

DTIC Science & Technology

2017-10-01

collected temporally close enough to imaging data in Phase 2 to be confidently incorporated in the planned statistical analyses, and (b) not unduly risk...Phase 2 to be confidently incorporated in the planned statistical analyses, and (b) not unduly risk attrition between Phase 1 and 2, we chose to hold...supervision is ongoing (since 9/2014). • Co-l Dr. Lerner’s 2nd year Clinical Psychology PhD students have participated in ADOS- 2 Introductory Clinical

GeoGIS : phase II.

DOT National Transportation Integrated Search

2009-12-01

A new web-based geotechnical Geographic Information System (GeoGIS) was developed and tested for the Alabama Department of Transportation (ALDOT) during Phase II of this research project. This web-based system stores geotechnical information about tr...

On-going clinical trials for elderly patients with a hematological malignancy: are we addressing the right end points?

PubMed

Hamaker, M E; Stauder, R; van Munster, B C

2014-03-01

Cancer societies and research cooperative groups worldwide have urged for the development of cancer trials that will address those outcome measures that are most relevant to older patients. We set out to determine the characteristics and study objectives of current clinical trials in hematological patients. The United States National Institutes of Health clinical trial registry was searched on 1 July 2013, for currently recruiting phase I, II or III clinical trials in hematological malignancies. Trial characteristics and study objectives were extracted from the registry website. In the 1207 clinical trials included in this overview, patient-centered outcome measures such as quality of life, health care utilization and functional capacity were only incorporated in a small number of trials (8%, 4% and 0.7% of trials, respectively). Even in trials developed exclusively for older patients, the primary focus lies on standard end points such as toxicity, efficacy and survival, while patient-centered outcome measures are included in less than one-fifth of studies. Currently on-going clinical trials in hematological malignancies are unlikely to significantly improve our knowledge of the optimal treatment of older patients as those outcome measures that are of primary importance to this patient population are still included in only a minority of studies. As a scientific community, we cannot continue to simply acknowledge this issue, but must all participate in taking the necessary steps to enable the delivery of evidence-based, tailor-made and patient-focused cancer care to our rapidly growing elderly patient population.

Investigational Antibody-Drug Conjugates for Treatment of B-lineage Malignancies.

PubMed

Herrera, Alex F; Molina, Arturo

2018-05-10

Antibody-drug conjugates (ADCs) are tripartite molecules consisting of a monoclonal antibody, a covalent linker, and a cytotoxic payload. ADC development has aimed to target the specificity inherent in antigen-antibody interactions to deliver potent cytotoxins preferentially to tumor cells and maximize antitumor activity and simultaneously minimize off-target toxicity. The earliest ADCs provided disappointing results in the clinic; however, the lessons learned regarding the need for human or humanized antibodies, more stable linkers, and greater potency payloads led to improved ADCs. Three ADCs, gemtuzumab ozogamicin, brentuximab vedotin (BV), and inotuzumab ozogamicin, have been approved for hematologic malignancies. Site-specific conjugation methods have now resulted in a new generation of more uniform, molecularly defined ADCs. These are expected to display improved in vivo properties and have recently entered the clinic. We reviewed investigational ADCs currently in clinical testing for the treatment of B-cell lineage malignancies, including leukemias, lymphomas, and multiple myeloma. The rationales for antigen targeting, data reported to date, current trial status, and preclinical results for several newer ADCs expected to enter first-in-human studies are presented. Owing to the large number of ongoing and reported BV clinical studies, only the studies of BV for diffuse large B-cell lymphoma and those combining BV with checkpoint inhibitors in B-lineage malignancies have been reviewed. With > 40 ongoing clinical trials and 7 investigational ADCs already having advanced to phase II studies, the role of ADCs in the armamentarium for the treatment of B-lineage malignancies continues to be elucidated. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

GPNMB expression in uveal melanoma: a potential for targeted therapy.

PubMed

Williams, Michelle D; Esmaeli, Bita; Soheili, Aydin; Simantov, Ronit; Gombos, Dan S; Bedikian, Agop Y; Hwu, Patrick

2010-06-01

Uveal melanoma is an aggressive disease without effective adjuvant therapy for metastases. Despite genomic differences between cutaneous and uveal melanomas, therapies based on shared biological factors could be effective against both tumor types. High expression of glycoprotein-NMB (GPNMB) in cutaneous melanomas led to the development of CDX-011 (glembatumumab vedotin), a fully human monoclonal antibody against the extracellular domain of GPNMB conjugated to the cytotoxic microtubule toxin monomethylauristatin E. Ongoing phase II trials suggest that CDX-011 has activity against advanced cutaneous melanomas. To determine the potential role of CDX-011 in uveal melanomas, we studied their GPNMB expression. Paraffin-embedded tissues from 22 uveal melanomas treated by enucleation from 2004-2007 at one institution were evaluated immunohistochemically for expression of GPNMB using biotinylated CDX-011 (unconjugated) antibody. Melanoma cells were evaluated for percentage and intensity of expression. Spectral imaging was used in one case with high melanin content. Clinical data were reviewed. Twelve women and 10 men with a median age of 58.7 years (range: 28-83 years) were included. Eighteen of 21 tumors evaluated immunohistochemically (85.7%) expressed GPNMB in 10-90% of tumor cells with variable intensity (5 tumors, 1+; 11, 2+; and 2, 3+). Eleven of 18 tumors (61.1%) expressed GPNMB in >or=50% of cells. Spectral imaging showed diffuse CDX-011 (unconjugated) reactivity in the remaining case. Uveal melanoma, like cutaneous melanoma, commonly expresses GPNMB. Ongoing clinical trials of CDX-011 should be extended to patients with metastatic uveal melanoma to determine potential efficacy in this subset of patients with melanoma.

Development and feasibility of the misuse, abuse, and diversion drug event reporting system (MADDERS®).

PubMed

Treister, Roi; Trudeau, Jeremiah J; Van Inwegen, Richard; Jones, Judith K; Katz, Nathaniel P

2016-12-01

Inappropriate use of analgesic drugs has become increasingly pervasive over the past decade. Currently, drug abuse potential is primarily assessed post-marketing; no validated tools are available to assess this potential in phase II and III clinical trials. This paper describes the development and feasibility testing of a Misuse, Abuse, and Diversion Drug Event Reporting System (MADDERS), which aims to identify potentially abuse-related events and classify them according to a recently developed classification scheme, allowing the quantification of these events in clinical trials. The system was initially conceived and designed with input from experts and patients, followed by field-testing to assess its feasibility and content validity in both completed and ongoing clinical trials. The results suggest that MADDERS is a feasible system with initial validity. It showed higher rates of the triggering events in subjects taking medications with known abuse potential than in patients taking medications without abuse potential. Additionally, experts agreed on the classification of most abuse-related events in MADDERS. MADDERS is a new systematic approach to collect information on potentially abuse-related events in clinical trials and classify them. The system has demonstrated feasibility for implementation. Additional research is ongoing to further evaluate its validity. Currently, there are no validated tools to assess drug abuse potential during clinical trials. Because of its ease of implementation, its systematic approach, and its preliminary validation results, MADDERS could provide such a tool for clinical trials. (Am J Addict 2016;25:641-651). © 2016 American Academy of Addiction Psychiatry.

On-going clinical trials for elderly patients with a hematological malignancy: are we addressing the right end points?†

PubMed Central

Hamaker, M. E.; Stauder, R.; van Munster, B. C.

2014-01-01

Background Cancer societies and research cooperative groups worldwide have urged for the development of cancer trials that will address those outcome measures that are most relevant to older patients. We set out to determine the characteristics and study objectives of current clinical trials in hematological patients. Method The United States National Institutes of Health clinical trial registry was searched on 1 July 2013, for currently recruiting phase I, II or III clinical trials in hematological malignancies. Trial characteristics and study objectives were extracted from the registry website. Results In the 1207 clinical trials included in this overview, patient-centered outcome measures such as quality of life, health care utilization and functional capacity were only incorporated in a small number of trials (8%, 4% and 0.7% of trials, respectively). Even in trials developed exclusively for older patients, the primary focus lies on standard end points such as toxicity, efficacy and survival, while patient-centered outcome measures are included in less than one-fifth of studies. Conclusion Currently on-going clinical trials in hematological malignancies are unlikely to significantly improve our knowledge of the optimal treatment of older patients as those outcome measures that are of primary importance to this patient population are still included in only a minority of studies. As a scientific community, we cannot continue to simply acknowledge this issue, but must all participate in taking the necessary steps to enable the delivery of evidence-based, tailor-made and patient-focused cancer care to our rapidly growing elderly patient population. PMID:24458474

Hazardous Materials Routing Study Phase II: Analysis of Hazardous Materials Truck Routes in Proximity to the Dallas Central Business District

DOT National Transportation Integrated Search

1985-10-01

This report summarizes the findings from the second phase of a two-part analysis of hazardous materials truck routes in the Dallas-Fort Worth area. Phase II of this study analyzes the risk of transporting hazardous materials on freeways and arterial ...

75 FR 4894 - Self-Regulatory Organizations; National Securities Clearing Corporation; Notice of Filing and...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-01-29

... activity.\\5\\ There will also be an increase in the monthly fee for the mutual fund Profile Phase II Service.... Profile Phase I transmits mutual fund price and rate information. Profile Phase II stores data elements such as accumulation, breakpoints, and commission eligibility that relate to mutual fund processing...

DEMONSTRATION OF FUEL CELLS TO RECOVER ENERGY FROM LANDFILL GAS: PHASE II. PRETREATMENT SYSTEM PERFORMANCE MEASUREMENT

EPA Science Inventory

The report describes Phase II of a demonstration of the utilization of commercial phosphoric acid fuel cells to recover energy from landfill gas. This phase consisted primarily of the construction and testing of a Gas Pretreatment Unit (GPU) whose function is to remove those impu...

Characterization of unpaved road condition through the use of remote sensing project - phase II, deliverable 8-D: final report.

DOT National Transportation Integrated Search

2016-03-07

Building on the success of developing a UAV based unpaved road assessment system in Phase I, the project team was awarded a Phase II project by the USDOT to focus on outreach and implementation. The project team added Valerie Lefler of Integrated Glo...

A Reliability Simulator for Radiation-Hard Microelectronics Development

DTIC Science & Technology

1991-07-01

1 3.0 PHASE II WORK PLANS ................................................................ 2... plan . The correlation experimental details including the devices utilized, the hot-carrier stressing and the wafer-level radiation correlation procedure...channel devices, and a new lifetime extrapolation method is demonstrated for p-channel devices. 3.0 PHASE II WORK PLANS The Phase 1I program consisted of

Galaxy interactions in compact groups - II. Abundance and kinematic anomalies in HCG 91c

NASA Astrophysics Data System (ADS)

Vogt, Frédéric P. A.; Dopita, Michael A.; Borthakur, Sanchayeeta; Verdes-Montenegro, Lourdes; Heckman, Timothy M.; Yun, Min S.; Chambers, Kenneth C.

2015-07-01

Galaxies in Hickson Compact Group 91 (HCG 91) were observed with the WiFeS integral field spectrograph as part of our ongoing campaign targeting the ionized gas physics and kinematics inside star-forming members of compact groups. Here, we report the discovery of H II regions with abundance and kinematic offsets in the otherwise unremarkable star-forming spiral HCG 91c. The optical emission line analysis of this galaxy reveals that at least three H II regions harbour an oxygen abundance ˜0.15 dex lower than expected from their immediate surroundings and from the abundance gradient present in the inner regions of HCG 91c. The same star-forming regions are also associated with a small kinematic offset in the form of a lag of 5-10 km s-1 with respect to the local circular rotation of the gas. H I observations of HCG 91 from the Very Large Array and broad-band optical images from Pan-STARRS (Panoramic Survey Telescope And Rapid Response System) suggest that HCG 91c is caught early in its interaction with the other members of HCG 91. We discuss different scenarios to explain the origin of the peculiar star-forming regions detected with WiFeS, and show that evidence points towards infalling and collapsing extraplanar gas clouds at the disc-halo interface, possibly as a consequence of long-range gravitational perturbations of HCG 91c from the other group members. As such, HCG 91c provides evidence that some of the perturbations possibly associated with the early phase of galaxy evolution in compact groups impact the star-forming disc locally, and on sub-kpc scales.

New York State Educational Information System (NYSEIS) Systems Design. Volume I, Phase II. Final Report.

ERIC Educational Resources Information Center

Price Waterhouse and Co., New York, NY.

This volume on Phase II of the New York State Educational Information System (NYSEIS) describes the Gross Systems Analysis and Design, which includes the general flow diagram and processing chart for each of the student, personnel, and financial subsystems. Volume II, Functional Specifications, includes input/output requirements and file…

Objective Lightning Probability Forecasting for Kennedy Space Center and Cape Canaveral Air Force Station, Phase III

NASA Technical Reports Server (NTRS)

Crawford, Winifred C.

2010-01-01

The AMU created new logistic regression equations in an effort to increase the skill of the Objective Lightning Forecast Tool developed in Phase II (Lambert 2007). One equation was created for each of five sub-seasons based on the daily lightning climatology instead of by month as was done in Phase II. The assumption was that these equations would capture the physical attributes that contribute to thunderstorm formation more so than monthly equations. However, the SS values in Section 5.3.2 showed that the Phase III equations had worse skill than the Phase II equations and, therefore, will not be transitioned into operations. The current Objective Lightning Forecast Tool developed in Phase II will continue to be used operationally in MIDDS. Three warm seasons were added to the Phase II dataset to increase the POR from 17 to 20 years (1989-2008), and data for October were included since the daily climatology showed lightning occurrence extending into that month. None of the three methods tested to determine the start of the subseason in each individual year were able to discern the start dates with consistent accuracy. Therefore, the start dates were determined by the daily climatology shown in Figure 10 and were the same in every year. The procedures used to create the predictors and develop the equations were identical to those in Phase II. The equations were made up of one to three predictors. TI and the flow regime probabilities were the top predictors followed by 1-day persistence, then VT and Ll. Each equation outperformed four other forecast methods by 7-57% using the verification dataset, but the new equations were outperformed by the Phase II equations in every sub-season. The reason for the degradation may be due to the fact that the same sub-season start dates were used in every year. It is likely there was overlap of sub-season days at the beginning and end of each defined sub-season in each individual year, which could very well affect equation performance.

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.

Phase I to II cross-induction of xenobiotic metabolizing enzymes: a feedforward control mechanism for potential hormetic responses.

PubMed

Zhang, Qiang; Pi, Jingbo; Woods, Courtney G; Andersen, Melvin E

2009-06-15

Hormetic responses to xenobiotic exposure likely occur as a result of overcompensation by the homeostatic control systems operating in biological organisms. However, the mechanisms underlying overcompensation that leads to hormesis are still unclear. A well-known homeostatic circuit in the cell is the gene induction network comprising phase I, II and III metabolizing enzymes, which are responsible for xenobiotic detoxification, and in many cases, bioactivation. By formulating a differential equation-based computational model, we investigated in this study whether hormesis can arise from the operation of this gene/enzyme network. The model consists of two feedback and one feedforward controls. With the phase I negative feedback control, xenobiotic X activates nuclear receptors to induce cytochrome P450 enzyme, which bioactivates X into a reactive metabolite X'. With the phase II negative feedback control, X' activates transcription factor Nrf2 to induce phase II enzymes such as glutathione S-transferase and glutamate cysteine ligase, etc., which participate in a set of reactions that lead to the metabolism of X' into a less toxic conjugate X''. The feedforward control involves phase I to II cross-induction, in which the parent chemical X can also induce phase II enzymes directly through the nuclear receptor and indirectly through transcriptionally upregulating Nrf2. As a result of the active feedforward control, a steady-state hormetic relationship readily arises between the concentrations of the reactive metabolite X' and the extracellular parent chemical X to which the cell is exposed. The shape of dose-response evolves over time from initially monotonically increasing to J-shaped at the final steady state-a temporal sequence consistent with adaptation-mediated hormesis. The magnitude of the hormetic response is enhanced by increases in the feedforward gain, but attenuated by increases in the bioactivation or phase II feedback loop gains. Our study suggests a possibly common mechanism for the hormetic responses observed with many mutagens/carcinogens whose activities require bioactivation by phase I enzymes. Feedforward control, often operating in combination with negative feedback regulation in a homeostatic system, may be a general control theme responsible for steady-state hormesis.

Perceiving the future news: Evidence for retrocausation

NASA Astrophysics Data System (ADS)

Graff, Dale E.; Cyrus, Patricia S.

2017-05-01

Thirty-three exploratory psi investigations were recently performed using Conscious State Psi and Dream State Psi protocols for photographic material that did not exist at the time of the psi sessions. Results would provide evidence for retrocausation if the future photographs had influenced the sessions' data. The psi targets were Associated Press (AP) news photographs published in a Reading, PA area newspaper on a specific page three days in the future. These photographs were taken one day after the psi sessions. Following each psi session, and prior to the photograph's existence, perceptions were recorded in project records and email transmitted for date validation. Feedback was provided when the photograph was published. There were two phases: Phase I was an informal investigation performed by the principle author to evaluate project feasibility. Phase II was a formal investigation with a colleague 1,000 miles from the principle author and the area newspaper location. All data were evaluated by direct comparison to the intended photographs using numerical assessment scales and noting unique features. Data from 21 of the 33 sessions (64%) yielded sketches and narratives with medium and high degrees of correlations with the future news photographs. A subsequent binary analysis using control photographs yielded p = 0.040. Visual informational content of these future newspaper photographs had interacted with the brain's cognitive processes in a retrocausal sense. The future photographs affected the sessions' data. A subconscious interaction between the future and the present or past may be an on-going feature of the mental and physical universe. Suggestions for follow-on investigations into retrocausation are provided.

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

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

Inclusion in Public Administration: Developing the Concept of Inclusion within a School of Accounts and Administration

ERIC Educational Resources Information Center

dos Santos, Mônica Pereira; de Melo, Sandra Cordeiro; Santiago, Mylene Cristina; Nazareth, Paula

2017-01-01

This study originates from ongoing action research that aims to develop institutional opportunities to reflect on and take decisions about inclusion in the School of Accounts and Administration of Rio de Janeiro's State Accounts Office. The research was organized in three phases. The first phase was an inservice course to sensitize professionals…

The fate of completed intentions.

PubMed

Anderson, Francis T; Einstein, Gilles O

2017-04-01

The goal of this research was to determine whether and how people deactivate prospective memory (PM) intentions after they have been completed. One view proposes that PM intentions can be deactivated after completion, such that they no longer come to mind and interfere with current tasks. Another view is that now irrelevant completed PM intentions exhibit persisting activation, and continue to be retrieved. In Experiment 1, participants were given a PM intention embedded within the ongoing task during Phase 1, after which participants were told either that the PM task had been completed or suspended until later. During Phase 2, participants were instructed to perform only the ongoing task and were periodically prompted to report their thoughts. Critically, the PM targets from Phase 1 reappeared in Phase 2. All of our measures, including thoughts reported about the PM task, supported the existence of persisting activation. In Experiment 2, we varied conditions that were expected to mitigate persisting activation. Despite our best attempts to promote deactivation, we found evidence for the persistence of spontaneous retrieval in all groups after intentions were completed. The theoretical and practical implications of this potential dark side to spontaneous retrieval are discussed.

The Andalusian Bipolar Family (ABiF) Study: Protocol and sample description.

PubMed

Guzman-Parra, Jose; Rivas, Fabio; Strohmaier, Jana; Forstner, Andreas; Streit, Fabian; Auburger, Georg; Propping, Peter; Orozco-Diaz, Guillermo; González, Maria José; Gil-Flores, Susana; Cabaleiro-Fabeiro, Francisco Javier; Del Río-Noriega, Francisco; Perez-Perez, Fermin; Haro-González, Jesus; de Diego-Otero, Yolanda; Romero-Sanchiz, Pablo; Moreno-Küstner, Berta; Cichon, Sven; Nöthen, Markus M; Rietschel, Marcella; Mayoral, Fermin

2017-06-12

Here, we present the first description of the Andalusian Bipolar Family (ABiF) Study. This longitudinal investigation of families from Andalusia, Spain commenced in 1997 with the aim of elucidating the molecular genetic causes of bipolar affective disorder. The cohort has since contributed to a number of key genetic findings, as reported in international journals. However, insight into the genetic underpinnings of the disorder in these families remains limited. In the initial 1997-2003 study phase, 100 multiplex bipolar disorder and other mood disorder families were recruited. The ongoing second phase of the project commenced in 2013, and involves follow-up of a subgroup of the originally recruited families. The aim of the follow-up investigation is to generate: i) longitudinal clinical data; ii) results from detailed neuropsychological assessments; and iii) a more extensive collection of biomaterials for future molecular biological studies. The ABiF Study will thus generate a valuable resource for future investigations into the aetiology of bipolar affective disorder; in particular the causes of high disease loading within multiply affected families. We discuss the value of this approach in terms of new technologies for the identification of high-penetrance genetic factors. These new technologies include exome and whole genome sequencing, and the use of induced pluripotent stem cells or model organisms to determine functional consequences. Copyright © 2017 SEP y SEPB. Publicado por Elsevier España, S.L.U. All rights reserved.

NLX-P101, an adeno-associated virus gene therapy encoding glutamic acid decarboxylase, for the potential treatment of Parkinson's disease.

PubMed

Diaz-Nido, Javier

2010-07-01

Parkinson's disease (PD) is a neurodegenerative disease affecting nigrostriatal dopaminergic neurons. Dopamine depletion in the striatum leads to functional changes in several deep brain nuclei, including the subthalamic nucleus (STN), which becomes disinhibited and perturbs the control of body movement. Although there is no cure for PD, some pharmacological and surgical treatments can significantly improve the functional ability of patients, particularly in the early stages of the disease. Among neurodegenerative diseases, PD is a particularly suitable target for gene therapy because the neuropathology is largely confined to a relatively small region of the brain. Neurologix Inc is developing NLX-P101 (AAV2-GAD), an adeno-associated viral vector encoding glutamic acid decarboxylase (GAD), for the potential therapy of PD. As GAD potentiates inhibitory neurotransmission from the STN, sustained expression of GAD in the STN by direct delivery of NLX-P101 decreases STN overactivation. This procedure was demonstrated to be a safe and efficient method of reducing motor deficits in animal models of PD. A phase I clinical trial has demonstrated that NLX-P101 was safe and indicated the efficacy of this approach in patients with PD. Results from an ongoing phase II clinical trial of NLX-P101 are awaited to establish the clinical efficacy of this gene therapy.

Peripherally acting opioid antagonists in the treatment of opiate-related constipation: a systematic review.

PubMed

Becker, Gerhild; Galandi, Daniel; Blum, Hubert E

2007-11-01

Many patients treated with opioids suffer from constipation. Opiate- or opioid-related constipation is not only a frequent but also a distressing symptom and difficult to treat. There is emerging evidence regarding a novel approach to the management of opiate-related constipation. The aim of this paper is to collect, critically appraise, and summarize the evidence on the effectiveness of recently developed peripherally acting micro-receptor antagonists in the treatment of opiate-related constipation. A comprehensive search of 11 computerized databases was conducted and efforts were made to identify unpublished and ongoing research. Twenty studies were identified; 13 were randomized controlled trials (RCTs) and 7 were Phase II studies assessing toxicity. Studies were mainly executed in healthy volunteers or members of methadone programs with opioid-induced constipation as a model to mimic the condition of patients on opioids. Two RCTs were conducted in hospice patients. Quality of study design and validity of the findings was assessed in all studies. Data show proof of concept but do not allow a definitive answer concerning the effectiveness of the peripherally acting micro-opioid antagonists methylnaltrexone and alvimopan in managing opiate-related constipation. Further research is needed. If future Phase III trials provide supportive data, opioid antagonists may become a standard therapeutic option for the treatment of opiate-related constipation in patients with advanced cancer.

Update on options for treatment of metastatic castration-resistant prostate cancer.

PubMed

Vishnu, Prakash; Tan, Winston W

2010-06-24

Prostate cancer is one of the most common cancers in men in US and European countries. Despite having a favorable prognosis, the incidence of incurable metastatic disease and mortality in the US is about 28,000 per year. Although hormone-based androgen deprivation therapies typically result in rapid responses, nearly all patients eventually develop progressive castration-resistant disease state. With readily available prostate-specific antigen (PSA) testing, most of these patients are asymptomatic and manifest progression simply as a rising PSA. In patients with castration-resistant prostate cancer (CRPC), the median survival is about 1-2 years, with improvements in survival seen mostly with docetaxel-based regimens. The purpose of this article is to review the recent developments in the treatment of advanced CRPC. Since the two landmark trials (TAX-327 and Southwest Oncology Group 99-16) in CRPC, several newer cytotoxic drugs (epothilones, satraplatin), targeted agents (abiraterone, MDV3100) and vaccines have been tested in phase II and III setting with promising results. The role of newer agents in the treatment of CRPC still needs to be validated by phase III trials, which are currently ongoing. Whilst the novel biomarkers, 'circulating tumor cells', have been shown to provide important prognostic information and are anticipated to be incorporated in future clinical decision-making, their exact utility and relevance calls for a larger prospective validation.

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).

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

PubMed

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

2011-08-01

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

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…

47 CFR 90.765 - Licenses term for Phase II licenses.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 220-222 MHz Band Policies Governing the Licensing and Use of Phase II Ea, Regional and Nationwide...(a), EA and Regional licenses authorized pursuant to § 90.761, and non-nationwide licenses authorized...

47 CFR 90.765 - Licenses term for Phase II licenses.

Code of Federal Regulations, 2011 CFR

2011-10-01

... 220-222 MHz Band Policies Governing the Licensing and Use of Phase II Ea, Regional and Nationwide...(a), EA and Regional licenses authorized pursuant to § 90.761, and non-nationwide licenses authorized...

Planning Targets for Phase II Watershed Implementation Plans

EPA Pesticide Factsheets

On August 1, 2011, EPA provided planning targets for nitrogen, phosphorus and sediment for the Phase II Watershed Implementation Plans (WIPs) of the Chesapeake Bay TMDL. This page provides the letters containing those planning targets.

Sears Point Tidal Marsh Restoration Project: Phase II

EPA Pesticide Factsheets

Information about the SFBWQP Sears Point Tidal Marsh Restoration Project: Phase II, part of an EPA competitive grant program to improve SF Bay water quality focused on restoring impaired waters and enhancing aquatic resources.

Pulsed Out of Awareness: EEG Alpha Oscillations Represent a Pulsed-Inhibition of Ongoing Cortical Processing

PubMed Central

Mathewson, Kyle E.; Lleras, Alejandro; Beck, Diane M.; Fabiani, Monica; Ro, Tony; Gratton, Gabriele

2011-01-01

Alpha oscillations are ubiquitous in the brain, but their role in cortical processing remains a matter of debate. Recently, evidence has begun to accumulate in support of a role for alpha oscillations in attention selection and control. Here we first review evidence that 8–12 Hz oscillations in the brain have a general inhibitory role in cognitive processing, with an emphasis on their role in visual processing. Then, we summarize the evidence in support of our recent proposal that alpha represents a pulsed-inhibition of ongoing neural activity. The phase of the ongoing electroencephalography can influence evoked activity and subsequent processing, and we propose that alpha exerts its inhibitory role through alternating microstates of inhibition and excitation. Finally, we discuss evidence that this pulsed-inhibition can be entrained to rhythmic stimuli in the environment, such that preferential processing occurs for stimuli at predictable moments. The entrainment of preferential phase may provide a mechanism for temporal attention in the brain. This pulsed inhibitory account of alpha has important implications for many common cognitive phenomena, such as the attentional blink, and seems to indicate that our visual experience may at least some times be coming through in waves. PMID:21779257

Dental and skeletal changes in patients with mandibular retrognathism following treatment with Herbst and pre-adjusted fixed appliance

PubMed Central

Vigorito, Fabio de Abreu; Dominguez, Gladys Cristina; Aidar, Luís Antônio de Arruda

2014-01-01

Objective To assess the dentoskeletal changes observed in treatment of Class II, division 1 malocclusion patients with mandibular retrognathism. Treatment was performed with the Herbst orthopedic appliance during 13 months (phase I) and pre-adjusted orthodontic fixed appliance (phase II). Methods Lateral cephalograms of 17 adolescents were taken in phase I onset (T1) and completion (T2); in the first thirteen months of phase II (T3) and in phase II completion (T4). Differences among the cephalometric variables were statistically analyzed (Bonferroni variance and multiple comparisons). Results From T1 to T4, 42% of overall maxillary growth was observed between T1 and T2 (P < 0.01), 40.3% between T2 and T3 (P < 0.05) and 17.7% between T3 and T4 (n.s.). As for overall mandibular movement, 48.2% was observed between T1 and T2 (P < 0.001) and 51.8% between T2 and T4 (P < 0.01) of which 15.1% was observed between T2 and T3 (n.s.) and 36.7% between T3 and T4 (P < 0.01). Class II molar relationship and overjet were properly corrected. The occlusal plane which rotated clockwise between T1 and T2, returned to its initial position between T2 and T3 remaining stable until T4. The mandibular plane inclination did not change at any time during treatment. Conclusion Mandibular growth was significantly greater in comparison to maxillary, allowing sagittal maxillomandibular adjustment. The dentoalveolar changes (upper molar) that overcorrected the malocclusion in phase I, partially recurred in phase II, but did not hinder correction of the malocclusion. Facial type was preserved. PMID:24713559

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.

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.

Chronic Iron Limitation Confers Transient Resistance to Oxidative Stress in Marine Diatoms.

PubMed

Graff van Creveld, Shiri; Rosenwasser, Shilo; Levin, Yishai; Vardi, Assaf

2016-10-01

Diatoms are single-celled, photosynthetic, bloom-forming algae that are responsible for at least 20% of global primary production. Nevertheless, more than 30% of the oceans are considered "ocean deserts" due to iron limitation. We used the diatom Phaeodactylum tricornutum as a model system to explore diatom's response to iron limitation and its interplay with susceptibility to oxidative stress. By analyzing physiological parameters and proteome profiling, we defined two distinct phases: short-term (<3 d, phase I) and chronic (>5 d, phase II) iron limitation. While at phase I no significant changes in physiological parameters were observed, molecular markers for iron starvation, such as Iron Starvation Induced Protein and flavodoxin, were highly up-regulated. At phase II, down-regulation of numerous iron-containing proteins was detected in parallel to reduction in growth rate, chlorophyll content, photosynthetic activity, respiration rate, and antioxidant capacity. Intriguingly, while application of oxidative stress to phase I and II iron-limited cells similarly oxidized the reduced glutathione (GSH) pool, phase II iron limitation exhibited transient resistance to oxidative stress, despite the down regulation of many antioxidant proteins. By comparing proteomic profiles of P. tricornutum under iron limitation and metatranscriptomic data of an iron enrichment experiment conducted in the Pacific Ocean, we propose that iron-limited cells in the natural environment resemble the phase II metabolic state. These results provide insights into the trade-off between optimal growth rate and susceptibility to oxidative stress in the response of diatoms to iron quota in the marine environment. © 2016 American Society of Plant Biologists. All Rights Reserved.

Evaluation of phase II toxicity identification evaluation methods for freshwater whole sediment and interstitial water.

PubMed

Phillips, Bryn M; Anderson, Brian S; Hunt, John W; Clark, Sara L; Voorhees, Jennifer P; Tjeerdema, Ron S; Casteline, Jane; Stewart, Margaret

2009-02-01

Phase I whole sediment toxicity identification evaluation (TIE) methods have been developed to characterize the cause of toxicity as organic chemicals, metals, or ammonia. In Phase II identification treatments, resins added to whole sediment to reduce toxicity caused by metals and organics can be separated and eluted much like solid-phase extraction (SPE) columns are eluted for interstitial water. In this study, formulated reference sediments spiked with toxic concentrations of copper, fluoranthene, and nonylphenol were subjected to whole sediment and interstitial water TIE treatments to evaluate Phase I and II TIE procedures for identifying the cause of toxicity to Hyalella azteca. Phase I TIE treatments consisted of adding adsorbent resins to whole sediment, and using SPE columns to remove spiked chemicals from interstitial water. Phase II treatments consisted of eluting resins and SPE columns and the preparation and testing of eluates for toxicity and chemistry. Whole sediment resins and SPE columns significantly reduced toxicity, and the eluates from all treatments contained toxic concentrations of the spiked chemical except for interstitial water fluoranthene. Toxic unit analysis based on median lethal concentrations (LC50s) allowed for the comparison of chemical concentrations among treatments, and demonstrated that the bioavailability of some chemicals was reduced in some samples and treatments. The concentration of fluoranthene in the resin eluate closely approximated the original interstitial water concentration, but the resin eluate concentrations of copper and nonylphenol were much higher than the original interstitial water concentrations. Phase II whole sediment TIE treatments provided complementary lines of evidence to the interstitial water TIE results.

Chronic Iron Limitation Confers Transient Resistance to Oxidative Stress in Marine Diatoms1

PubMed Central

Graff van Creveld, Shiri; Rosenwasser, Shilo; Vardi, Assaf

2016-01-01

Diatoms are single-celled, photosynthetic, bloom-forming algae that are responsible for at least 20% of global primary production. Nevertheless, more than 30% of the oceans are considered “ocean deserts” due to iron limitation. We used the diatom Phaeodactylum tricornutum as a model system to explore diatom’s response to iron limitation and its interplay with susceptibility to oxidative stress. By analyzing physiological parameters and proteome profiling, we defined two distinct phases: short-term (<3 d, phase I) and chronic (>5 d, phase II) iron limitation. While at phase I no significant changes in physiological parameters were observed, molecular markers for iron starvation, such as Iron Starvation Induced Protein and flavodoxin, were highly up-regulated. At phase II, down-regulation of numerous iron-containing proteins was detected in parallel to reduction in growth rate, chlorophyll content, photosynthetic activity, respiration rate, and antioxidant capacity. Intriguingly, while application of oxidative stress to phase I and II iron-limited cells similarly oxidized the reduced glutathione (GSH) pool, phase II iron limitation exhibited transient resistance to oxidative stress, despite the down regulation of many antioxidant proteins. By comparing proteomic profiles of P. tricornutum under iron limitation and metatranscriptomic data of an iron enrichment experiment conducted in the Pacific Ocean, we propose that iron-limited cells in the natural environment resemble the phase II metabolic state. These results provide insights into the trade-off between optimal growth rate and susceptibility to oxidative stress in the response of diatoms to iron quota in the marine environment. PMID:27503604

SH-2F LAMPS Instructional Systems Development: Phase II. Final Report.

ERIC Educational Resources Information Center

Gibbons, Andrew S.; Hymes, Jonah P.

This project was one of four aircrew training development projects in a continuing study of the methodology, effectiveness, and resource requirements of the Instructional Systems Development (ISD) process. This report covers the Phase II activities of a two-phase project for the development of aircrew training for SH-2F anti-submarine warfare…

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...

An Experimental Evaluation of Hyperactivity and Food Additives. 1977-Phase II.

ERIC Educational Resources Information Center

Harley, J. Preston; And Others

Phase II of a study on the effectiveness of B. Feingold's recommended diet for hyperactive children involved the nine children (mean age 9 years) who had shown the "best" response to diet manipulation in Phase I. Each child served as his own control and was challenged with specified amounts of placebo and artificial color containing food…

Job Aids: Descriptive Authoring Flowcharts for Phase II--DESIGN 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 second 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 II.1 through II.4. The introduction includes definitions;…

Thermal, spectroscopic and structural characterization of isostructural phase transition in 4-hydroxybenzaldehyde

NASA Astrophysics Data System (ADS)

Panicker, Lata

2018-05-01

Polycrystalline samples of 4-hydroxybenzaldehyde (4-HOBAL) were investigated using differential scanning calorimeter (DSC), Raman spectroscopy and X-ray powder diffraction. The DSC data indicated that 4-HOBAL on heating undergoes a polymorphic transformation from polymorph I to polymorph II. The polymorph II formed remains metastable at ambient condition and transforms to polymorph I when annealed at ambient temperature for more than seven days. The structural information of polymorphs I and II obtained using its X-ray powder diffraction patterns indicated that 4-HOBAL undergoes an isostructural phase transition from polymorph I (monoclinic, P21/c) to polymorph II (monoclinic, P21/c). Raman data suggest that this structural change is associated with some change in its molecular interactions. Thus, in 4-HOBAL the polymorphic phase transformation (II to I) even though energetically favoured is kinetically hindered.

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

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

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

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

Preparation and characterization of magnetic nanocomposite of Schiff base/silica/magnetite as a preconcentration phase for the trace determination of heavy metal ions in water, food and biological samples using atomic absorption spectrometry.

PubMed

Bagheri, Hasan; Afkhami, Abbas; Saber-Tehrani, Mohammad; Khoshsafar, Hosein

2012-08-15

A versatile and robust solid phase with both magnetic property and a very high adsorption capacity is presented on the basis of modification of iron oxide-silica magnetic particles with a newly synthesized Schiff base (Fe(3)O(4)/SiO(2)/L). The structure of the resulting product was confirmed by Fourier transform infrared (FT-IR) spectra, X-ray diffraction (XRD) spectrometry and transmission electron microscopy (TEM). We developed an efficient and cost-effective method for the preconcentration of trace amounts of Pb(II), Cd(II) and Cu(II) in environmental and biological samples using this novel magnetic solid phase. Prepared magnetic solid phase is an ideal support because it has a large surface area, good selectivity and can be easily retrieved from large volumes of aqueous solutions. The possible parameters affecting the enrichment were optimized. Under the optimal conditions, the method detection limit was 0.14, 0.19 and 0.12 μg L(-1) for Pb(II), Cd(II) and Cu(II) ions, respectively. The established method has been successfully applied to analyze real samples, and satisfactory results were obtained. All these indicated that this magnetic phase had a great potential in environmental and biological fields. Copyright © 2012 Elsevier B.V. All rights reserved.

Phase I/II Study of Weekly Oraxol for the Second-Line Treatment of Patients With Metastatic or Recurrent Gastric Cancer.

PubMed

Lee, Keun-Wook; Lee, Kyung Hee; Zang, Dae Young; Park, Young Iee; Shin, Dong Bok; Kim, Jin Won; Im, Seock-Ah; Koh, Sung Ae; Yu, Kyung-Sang; Cho, Joo-Youn; Jung, Jin-A; Bang, Yung-Jue

2015-08-01

Oraxol consists of paclitaxel and HM30181A, a P-glycoprotein inhibitor, to increase the oral bioavailability of paclitaxel. This phase I/II study (HM-OXL-201) was conducted to determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of Oraxol. In addition, we investigated the efficacy and safety of Oraxol as second-line chemotherapy for metastatic or recurrent gastric cancer (GC). In the phase I component, paclitaxel was orally administered at escalating doses (90, 120, or 150 mg/m(2) per day) with a fixed dose (15 mg/day) of HM30181A. Oraxol was administrated 6 times per cycle (days 1, 2, 8, 9, 15, and 16) every 4 weeks. In the phase II component, the efficacy and safety of Oraxol were evaluated. In the phase I component, the MTD could not be determined. Based on toxicity and pharmacokinetic data, the RP2D of oral paclitaxel was determined to be 150 mg/m(2). In the phase II component, 4 of 43 patients (9.3%) achieved partial responses. Median progression-free survival and overall survival were 2.6 and 10.7 months, respectively. Toxicity profiles were favorable, and the most common drug-related adverse events (grade ≥3) were neutropenia and diarrhea. Oraxol exhibited modest efficacy and favorable toxicity profiles as second-line chemotherapy for GC. ©AlphaMed Press; the data published online to support this summary is the property of the authors.

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.

10 CFR 110.42 - Export licensing criteria.

Code of Federal Regulations, 2010 CFR

2010-01-01

...) through (9) of appendix A to this part, when exported separately from the items described in paragraphs (1... in the United States. (9)(i) Except as provided in paragraph (a)(9)(ii) of this section, with respect... ongoing and planned experiments and isotope production to be conducted in the reactor without a large...

10 CFR 110.42 - Export licensing criteria.

Code of Federal Regulations, 2011 CFR

2011-01-01

...) through (9) of appendix A to this part, when exported separately from the items described in paragraphs (1... in the United States. (9)(i) Except as provided in paragraph (a)(9)(ii) of this section, with respect... ongoing and planned experiments and isotope production to be conducted in the reactor without a large...

Forward to the Past in New Zealand Teacher Education.

ERIC Educational Resources Information Center

Openshaw, Roger

1999-01-01

Illustrates how the culture of teacher education developed after World War II in New Zealand, highlighting the former Palmerston North College of Education and contending that the culture was shaped by: the ongoing requirement to train (at minimal cost) competent elementary teachers in accordance with government laws of supply and demand and…

South Bay Salt Pond Restoration, Phase II at Ravenswood

EPA Pesticide Factsheets

Information about the South Bay Salt Pond Restoration Project: Phase II Construction at Ravenswood, part of an EPA competitive grant program to improve SF Bay water quality focused on restoring impaired waters and enhancing aquatic resources.

Carbon footprint estimator, phase II : volume II - technical appendices.

DOT National Transportation Integrated Search

2014-03-01

The GASCAP model was developed to provide a software tool for analysis of the life-cycle GHG : emissions associated with the construction and maintenance of transportation projects. This phase : of development included techniques for estimating emiss...

Morristown Alternative Transportation Study Phase II.

DOT National Transportation Integrated Search

2005-10-14

This report summarizes the Phase II planning effort conducted by the park and the US Department of Transportation's Volpe Center (the Volpe Center) to articulate a viable park-community pilot transit service for Morristown National Historical Park. M...

The topological pressure-temperature phase diagram of ritonavir, an extraordinary case of crystalline dimorphism.

PubMed

Céolin, R; Rietveld, I B

2015-01-01

A topological pressure-temperature phase diagram involving the phase relationships of ritonavir forms I and II has been constructed using experimental calorimetric and volumetric data available from the literature. The triple point I-II-liquid is located at a temperature of about 407 K and a pressure as extraordinarily small as 17.5 MPa (175 bar). Thus, the less soluble solid phase (form II) will become metastable on increasing pressure. At room temperature, form I becomes stable around 100 MPa indicating that form II may turn into form I at a relatively low pressure of 1000 bar, which may occur under processing conditions such as mixing or grinding. This case is a good example for which a proper thermodynamic evaluation trumps "rules of thumb" such as the density rule. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

Detailed validation of the bidirectional effect in various Case I and Case II waters.

PubMed

Gleason, Arthur C R; Voss, Kenneth J; Gordon, Howard R; Twardowski, Michael; Sullivan, James; Trees, Charles; Weidemann, Alan; Berthon, Jean-François; Clark, Dennis; Lee, Zhong-Ping

2012-03-26

Simulated bidirectional reflectance distribution functions (BRDF) were compared with measurements made just beneath the water's surface. In Case I water, the set of simulations that varied the particle scattering phase function depending on chlorophyll concentration agreed more closely with the data than other models. In Case II water, however, the simulations using fixed phase functions agreed well with the data and were nearly indistinguishable from each other, on average. The results suggest that BRDF corrections in Case II water are feasible using single, average, particle scattering phase functions, but that the existing approach using variable particle scattering phase functions is still warranted in Case I water.

Gene Therapy for Color Blindness.

PubMed

Hassall, Mark M; Barnard, Alun R; MacLaren, Robert E

2017-12-01

Achromatopsia is a rare congenital cause of vision loss due to isolated cone photoreceptor dysfunction. The most common underlying genetic mutations are autosomal recessive changes in CNGA3 , CNGB3 , GNAT2 , PDE6H , PDE6C , or ATF6 . Animal models of Cnga3 , Cngb3 , and Gnat2 have been rescued using AAV gene therapy; showing partial restoration of cone electrophysiology and integration of this new photopic vision in reflexive and behavioral visual tests. Three gene therapy phase I/II trials are currently being conducted in human patients in the USA, the UK, and Germany. This review details the AAV gene therapy treatments of achromatopsia to date. We also present novel data showing rescue of a Cnga3 -/- mouse model using an rAAV.CBA.CNGA3 vector. We conclude by synthesizing the implications of this animal work for ongoing human trials, particularly, the challenge of restoring integrated cone retinofugal pathways in an adult visual system. The evidence to date suggests that gene therapy for achromatopsia will need to be applied early in childhood to be effective.

Nivolumab for the treatment of colorectal cancer.

PubMed

Smith, Kortnye Maureen; Desai, Jayesh

2018-05-24

Despite a variety of therapies for advanced metastatic colorectal cancer being available, the outcomes in this malignancy remain sub-optimal. Immunotherapy has been slow to impact the management of this patient group. Checkpoint inhibitors, such as nivolumab, have had disappointing results when used broadly. However, for the subset of patients with microsatellite unstable colorectal cancer the use of checkpoint inhibitors such as nivolumab appears to be transformative, and will provide a new therapeutic option for patient with advanced disease. Areas covered: Nivolumab gained regulatory approval for the treatment of dMMR/MSI-H metastatic colorectal cancer in mid 2017. The current review will summarize the clinical evidence of checkpoint inhibitors in metastatic colorectal cancer, with a focus on nivolumab. Expert commentary: For patients with dMMR/MSI-H mCRC the use of nivolumab has now been shown to have objective and sustained clinical responses in a pivotal phase II trial. While additional data is limited, the therapeutic role for augmenting an immune response in metastatic colorectal cancer is likely to continue to expand. Further combination trials of nivolumab with immunologic and non-immunologic agents are ongoing.

Mechanochemical induced structural changes in sucrose using the rotational diamond anvil cell

NASA Astrophysics Data System (ADS)

Ciezak-Jenkins, Jennifer A.; Jenkins, Timothy A.

2018-02-01

The response of sucrose to high-pressure and shear conditions has been studied in a rotational diamond anvil cell. Previous experiments conducted by Bridgman and Teller showed divergent behavior in regard to the existence of a rheological explosion under mechanochemical stimuli. Raman spectroscopy confirmed the existence of the isostructural Phase I to Phase II transition near 5 GPa. When subjected to high-pressure and shear, Raman spectra of Phase I showed evidence that while the sucrose molecule underwent significant molecular deformation, there was no evidence of a complete chemical reaction. In contrast, Phase II showed a near-total loss of the in-situ Raman signal in response to shear, suggesting the onset of amorphization or decomposition. The divergent behaviors of Phase I and Phase II are examined in light of the differences in the hydrogen bonding and plasticity of the material.

Can blood and semen presepsin levels in males predict pregnancy in couples undergoing intra-cytoplasmic sperm injection?

PubMed Central

Ovayolu, Ali; Arslanbuğa, Cansev Yilmaz; Gun, Ismet; Devranoglu, Belgin; Ozdemir, Arman; Cakar, Sule Eren

2016-01-01

Objective: To determine whether semen and plasma presepsin values measured in men with normozoospermia and oligoasthenospermia undergoing invitro-fertilization would be helpful in predicting ongoing pregnancy and live birth. Methods: Group-I was defined as patients who had pregnancy after treatment and Group-II comprised those with no pregnancy. Semen and blood presepsin values were subsequently compared between the groups. Parametric comparisons were performed using Student’s t-test, and non-parametric comparisons were conducted using the Mann-Whitney U test. Results: There were 42 patients in Group-I and 72 in Group-II. In the context of successful pregnancy and live birth, semen presepsin values were statistically significantly higher in Group-I than in Group-II (p= 0.004 and p= 0.037, respectively). The most appropriate semen presepsin cut-off value for predicting both ongoing pregnancy and live birth was calculated as 199 pg/mL. Accordingly, their sensitivity was 64.5% to 59.3%, their specificity was 57.0% to 54.2%, and their positive predictive value was 37.0% to 29.6%, respectively; their negative predictive value was 80.4% in both instances. Conclusion: Semen presepsin values could be a new marker that may enable the prediction of successful pregnancy and/or live birth. Its negative predictive values are especially high. PMID:27882005

The rapid expansion of (mainstream) health psychology in France: Historical foundations.

PubMed

Santiago-Delefosse, Marie; Del Rio Carral, Maria

2018-03-01

This article traces the historical evolution of ongoing theoretical debates in psychology in France from the 1940s until today. Its aim is to show how the conjunction of certain conditions led to a rapid expansion of American-derived mainstream health psychology during the 1980s. The authors describe the French context in the post-World War II period and outline the implementation of 'clinical psychology in health settings' in the 1950s, under the influence of Daniel Lagache. The strong critiques of the new psychology profession in the 1950s, 1960s and 1970s are examined. Our conclusion reflects upon future implications of ongoing rivalries between different approaches to psychology.

Pavement performance evaluation, phase II : data collection.

DOT National Transportation Integrated Search

2008-12-01

Phase I and II of this study tested approximately 1500 rehabilitated pavements (asphalt and PCC) : throughout the State. These pavements ranged from 5 to 15 years old and were intended to develop a : snapshot of how various rehabilitations were perfo...

Improving traffic safety culture in Iowa : phase II.

DOT National Transportation Integrated Search

2013-07-01

Phase II of Improving Traffic Safety Culture in Iowa focuses on producing actions that will improve the traffic safety culture across the state, and involves collaboration among the three large public universities in Iowa: Iowa State University, Univ...

South Bay Salt Pond Tidal Wetland Restoration Phase II Planning

EPA Pesticide Factsheets

Information about the SFBWQP South Bay Salt Pond Tidal Wetland Restoration Phase II Planning project, part of an EPA competitive grant program to improve SF Bay water quality focused on restoring impaired waters and enhancing aquatic re

Thermodynamic, crystallographic, and dielectric study of the nature of glass transitions in cyclo-octanol

NASA Astrophysics Data System (ADS)

Puertas, Ricardo; Rute, Maria A.; Salud, Josep; López, David O.; Diez, Sergio; van Miltenburg, J. Kees; Pardo, Luis C.; Tamarit, Josep Ll.; Barrio, Maria; Pérez-Jubindo, Miguel A.; de La Fuente, Maria R.

2004-06-01

The stable solid polymorphism of cyclooctanol (C8H16O, for short C8 OH) is revealed to be a complex problem and only two stable solid phases, denoted on cooling from the liquid as phases I and II, are found using static (thermodynamic and x-ray diffraction) as well as dynamic (dielectric spectroscopy) experimental techniques. Both solid phases are known to exhibit glass transitions if they are cooled down fast enough to prevent transition to ordered crystalline states. Although glass transitions corresponding to both phases had been well documented by means of specific heat measurements, x-ray measurements constitute, as far as we know, the first evidence from the structural point of view. In addition, a great amount of dielectric works devoted to phase I and its glass transition, were published in the past but next to nothing relating to the dielectric properties of phase II and its glass transition. The nature of the disorder of phase II will be discussed.

"The Trampoline Tree and the Swamp Monster with 18 Heads": Outdoor Play in the Foundation Stage and Foundation Phase

ERIC Educational Resources Information Center

Waller, Tim

2007-01-01

This paper considers pedagogy and outdoor play in the early years. The particular focus is on the specific features and benefits of outdoor play in the Foundation Stage (England) and Foundation Phase (Wales). The paper will draw on current international literature and evidence from outdoor learning constructed in an ongoing research project in two…

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

PubMed

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

2017-01-01

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

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

PubMed Central

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

2017-01-01

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

Characterization of pH dependent Mn(II) oxidation strategies and formation of a bixbyite-like phase by Mesorhizobium australicum T-G1

USGS Publications Warehouse

Bohu, Tsing; Santelli, Cara M; Akob, Denise M.; Neu, Thomas R; Ciobota, Valerian; Rösch, Petra; Popp, Jürgen; Nietzsche, Sándor; Küsel, Kirsten

2015-01-01

Despite the ubiquity of Mn oxides in natural environments, there are only a few observations of biological Mn(II) oxidation at pH < 6. The lack of low pH Mn-oxidizing bacteria (MOB) isolates limits our understanding of how pH influences biological Mn(II) oxidation in extreme environments. Here, we report that a novel MOB isolate, Mesorhizobium australicum strain T-G1, isolated from an acidic and metalliferous uranium mining area, can oxidize Mn(II) at both acidic and neutral pH using different enzymatic pathways. X-ray diffraction, Raman spectroscopy, and scanning electron microscopy with energy dispersive X-ray spectroscopy revealed that T-G1 initiated bixbyite-like Mn oxide formation at pH 5.5 which coincided with multi-copper oxidase expression from early exponential phase to late stationary phase. In contrast, reactive oxygen species (ROS), particularly superoxide, appeared to be more important for T-G1 mediated Mn(II) oxidation at neutral pH. ROS was produced in parallel with the occurrence of Mn(II) oxidation at pH 7.2 from early stationary phase. Solid phase Mn oxides did not precipitate, which is consistent with the presence of a high amount of H2O2 and lower activity of catalase in the liquid culture at pH 7.2. Our results show that M. australicum T-G1, an acid tolerant MOB, can initiate Mn(II) oxidation by varying its oxidation mechanisms depending on the pH and may play an important role in low pH manganese biogeochemical cycling.

Characterization of pH dependent Mn(II) oxidation strategies and formation of a bixbyite-like phase by Mesorhizobium australicum T-G1.

PubMed

Bohu, Tsing; Santelli, Cara M; Akob, Denise M; Neu, Thomas R; Ciobota, Valerian; Rösch, Petra; Popp, Jürgen; Nietzsche, Sándor; Küsel, Kirsten

2015-01-01

Despite the ubiquity of Mn oxides in natural environments, there are only a few observations of biological Mn(II) oxidation at pH < 6. The lack of low pH Mn-oxidizing bacteria (MOB) isolates limits our understanding of how pH influences biological Mn(II) oxidation in extreme environments. Here, we report that a novel MOB isolate, Mesorhizobium australicum strain T-G1, isolated from an acidic and metalliferous uranium mining area, can oxidize Mn(II) at both acidic and neutral pH using different enzymatic pathways. X-ray diffraction, Raman spectroscopy, and scanning electron microscopy with energy dispersive X-ray spectroscopy revealed that T-G1 initiated bixbyite-like Mn oxide formation at pH 5.5 which coincided with multi-copper oxidase expression from early exponential phase to late stationary phase. In contrast, reactive oxygen species (ROS), particularly superoxide, appeared to be more important for T-G1 mediated Mn(II) oxidation at neutral pH. ROS was produced in parallel with the occurrence of Mn(II) oxidation at pH 7.2 from early stationary phase. Solid phase Mn oxides did not precipitate, which is consistent with the presence of a high amount of H2O2 and lower activity of catalase in the liquid culture at pH 7.2. Our results show that M. australicum T-G1, an acid tolerant MOB, can initiate Mn(II) oxidation by varying its oxidation mechanisms depending on the pH and may play an important role in low pH manganese biogeochemical cycling.

Specific threonine-4 phosphorylation and function of RNA polymerase II CTD during M phase progression

PubMed Central

Hintermair, Corinna; Voß, Kirsten; Forné, Ignasi; Heidemann, Martin; Flatley, Andrew; Kremmer, Elisabeth; Imhof, Axel; Eick, Dirk

2016-01-01

Dynamic phosphorylation of Tyr1-Ser2-Pro3-Thr4-Ser5-Pro6-Ser7 heptad-repeats in the C-terminal domain (CTD) of the large subunit coordinates progression of RNA polymerase (Pol) II through the transcription cycle. Here, we describe an M phase-specific form of Pol II phosphorylated at Thr4, but not at Tyr1, Ser2, Ser5, and Ser7 residues. Thr4 phosphorylated Pol II binds to centrosomes and midbody and interacts with the Thr4-specific Polo-like kinase 1. Binding of Pol II to centrosomes does not require the CTD but may involve subunits of the non-canonical R2TP-Prefoldin-like complex, which bind to and co-localize with Pol II at centrosomes. CTD Thr4 mutants, but not Ser2 and Ser5 mutants, display severe mitosis and cytokinesis defects characterized by multipolar spindles and polyploid cells. We conclude that proper M phase progression of cells requires binding of Pol II to centrosomes to facilitate regulation of mitosis and cytokinesis in a CTD Thr4-P dependent manner. PMID:27264542

Specific threonine-4 phosphorylation and function of RNA polymerase II CTD during M phase progression.

PubMed

Hintermair, Corinna; Voß, Kirsten; Forné, Ignasi; Heidemann, Martin; Flatley, Andrew; Kremmer, Elisabeth; Imhof, Axel; Eick, Dirk

2016-06-06

Dynamic phosphorylation of Tyr1-Ser2-Pro3-Thr4-Ser5-Pro6-Ser7 heptad-repeats in the C-terminal domain (CTD) of the large subunit coordinates progression of RNA polymerase (Pol) II through the transcription cycle. Here, we describe an M phase-specific form of Pol II phosphorylated at Thr4, but not at Tyr1, Ser2, Ser5, and Ser7 residues. Thr4 phosphorylated Pol II binds to centrosomes and midbody and interacts with the Thr4-specific Polo-like kinase 1. Binding of Pol II to centrosomes does not require the CTD but may involve subunits of the non-canonical R2TP-Prefoldin-like complex, which bind to and co-localize with Pol II at centrosomes. CTD Thr4 mutants, but not Ser2 and Ser5 mutants, display severe mitosis and cytokinesis defects characterized by multipolar spindles and polyploid cells. We conclude that proper M phase progression of cells requires binding of Pol II to centrosomes to facilitate regulation of mitosis and cytokinesis in a CTD Thr4-P dependent manner.

Implementation of a Proficiency-Based Diploma System in Maine: Phase II--District Level Analysis

ERIC Educational Resources Information Center

Silvernail, David L.; Stump, Erika K.; McCafferty, Anita Stewart; Hawes, Kathryn M.

2014-01-01

This report describes the findings from Phase II of a study of Maine's implementation of a proficiency-based diploma system. At the request of the Joint Standing Committee on Education and Cultural Affairs of the Maine Legislature, the Maine Policy Research Institute (MEPRI) has conducted a two-phased study of the implementation of Maine law…

40 CFR 76.8 - Early election for Group 1, Phase II boilers.

Code of Federal Regulations, 2010 CFR

2010-07-01

... PROGRAMS (CONTINUED) ACID RAIN NITROGEN OXIDES EMISSION REDUCTION PROGRAM § 76.8 Early election for Group 1... plan and: (i) If a Phase I Acid Rain permit governing the source at which the unit is located has been... chapter to include the early election plan; or (ii) If a Phase I Acid Rain permit governing the source at...

40 CFR 76.8 - Early election for Group 1, Phase II boilers.

Code of Federal Regulations, 2014 CFR

2014-07-01

... PROGRAMS (CONTINUED) ACID RAIN NITROGEN OXIDES EMISSION REDUCTION PROGRAM § 76.8 Early election for Group 1... plan and: (i) If a Phase I Acid Rain permit governing the source at which the unit is located has been... chapter to include the early election plan; or (ii) If a Phase I Acid Rain permit governing the source at...

40 CFR 76.8 - Early election for Group 1, Phase II boilers.

Code of Federal Regulations, 2011 CFR

2011-07-01

... PROGRAMS (CONTINUED) ACID RAIN NITROGEN OXIDES EMISSION REDUCTION PROGRAM § 76.8 Early election for Group 1... plan and: (i) If a Phase I Acid Rain permit governing the source at which the unit is located has been... chapter to include the early election plan; or (ii) If a Phase I Acid Rain permit governing the source at...

40 CFR 76.8 - Early election for Group 1, Phase II boilers.

Code of Federal Regulations, 2012 CFR

2012-07-01

... PROGRAMS (CONTINUED) ACID RAIN NITROGEN OXIDES EMISSION REDUCTION PROGRAM § 76.8 Early election for Group 1... plan and: (i) If a Phase I Acid Rain permit governing the source at which the unit is located has been... chapter to include the early election plan; or (ii) If a Phase I Acid Rain permit governing the source at...

40 CFR 76.8 - Early election for Group 1, Phase II boilers.

Code of Federal Regulations, 2013 CFR

2013-07-01

... PROGRAMS (CONTINUED) ACID RAIN NITROGEN OXIDES EMISSION REDUCTION PROGRAM § 76.8 Early election for Group 1... plan and: (i) If a Phase I Acid Rain permit governing the source at which the unit is located has been... chapter to include the early election plan; or (ii) If a Phase I Acid Rain permit governing the source at...

Extension and Public Service in the University of Illinois. Phase II Report.

ERIC Educational Resources Information Center

Illinois Univ., Urbana.

Phase II of the report on the problem outlined in Phase I deals with specific recommendations for expanding and improving the extension and public service functions of the University of Illinois. To be effective, the university needs a master plan in which the four essential ingredients must be (1) broad, strong and explicit policy commitments by…

Phase II trial of veliparib in patients with previously treated BRCA-mutated pancreas ductal adenocarcinoma.

PubMed

Lowery, Maeve A; Kelsen, David P; Capanu, Marinela; Smith, Sloane C; Lee, Jonathan W; Stadler, Zsofia K; Moore, Malcolm J; Kindler, Hedy L; Golan, Talia; Segal, Amiel; Maynard, Hannah; Hollywood, Ellen; Moynahan, MaryEllen; Salo-Mullen, Erin E; Do, Richard Kinh Gian; Chen, Alice P; Yu, Kenneth H; Tang, Laura H; O'Reilly, Eileen M

2018-01-01

BRCA-associated cancers have increased sensitivity to poly(ADP-ribose) polymerase inhibitors (PARPis). This single arm, non-randomised, multicentre phase II trial evaluated the response rate of veliparib in patients with previously treated BRCA1/2- or PALB2-mutant pancreatic adenocarcinoma (PDAC). Patients with stage III/IV PDAC and known germline BRCA1/2 or PALB2 mutation, 1-2 lines of treatment, Eastern Cooperative Oncology Group 0-2, were enrolled. Veliparib was dosed at a volume of 300 mg twice-daily (N = 3), then 400 mg twice-daily (N = 15) days 1-28. The primary end-point was to determine the response rate of veliparib; secondary end-points included progression-free survival (PFS), duration of response, overall survival (OS) and safety. Sixteen patients were enrolled; male N = 8 (50%). Median age was 52 years (range 43-77). Five (31%) had a BRCA1 and 11 (69%) had a BRCA2 mutation. Fourteen (88%) patients had received prior platinum-based therapy. No confirmed partial responses (PRs) were seen: one (6%) unconfirmed PR was observed at 4 months with disease progression (PD) at 6 months; four (25%) had stable disease (SD), whereas 11 (69%) had PD as best response including one with clinical PD. Median PFS was 1.7 months (95% confidence interval [CI] 1.57-1.83) and median OS was 3.1 months (95% CI 1.9-4.1). Six (38%) patients had grade III toxicity, including fatigue (N = 3), haematology (N = 2) and nausea (N = 1). Veliparib was well tolerated, but no confirmed response was observed although four (25%) patients remained on study with SD for ≥ 4 months. Additional strategies in this population are needed, and ongoing trials are evaluating PARPis combined with chemotherapy (NCT01585805) and as a maintenance strategy (NCT02184195). Copyright © 2017 Elsevier Ltd. All rights reserved.

A Report on the Navy SBIR Program: Best Practices, Roadblocks and Recommendations for Technology Transition

DTIC Science & Technology

2008-04-01

a recommendation to the Phase I Sponsor, the NAVSEA SBIR Program Manager, and the PCO between 90 and 180 days after Phase I contract execution...determine eligibility for Phase II and send recommendations to sponsor Between 90 and 180 days after contract execution PCO Invites Phase II Proposals...manning study to evaluate the claim of inadequate numbers of contracting personnel. Although there were symptoms that contract delays were in part

Comparison between the phase I and phase II 6 m coke oven batteries of C. Still type in China Steel Corporation

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

Chiao-Hwa, H.; Tai-Heng, C.; Cheng-Hwa, L.

1983-01-01

The 98 ovens built for phase II batteries at China Steel Corporation show significant improvements over those of phase I, although they are operated in series with these. Improvements discussed in this paper include those associated with the single collection main, water sealing for the ascension pipe, aspiration by high pressure flushing liquor, self-sealing doors, wall head armour structures, waste gas flues and thermal efficiency.

The transition between the niche and neutral regimes in ecology

PubMed Central

Fisher, Charles K.; Mehta, Pankaj

2014-01-01

An ongoing debate in ecology concerns the impacts of ecological drift and selection on community assembly. Here, we show that there is a transition in diverse ecological communities between a selection-dominated regime (the niche phase) and a drift-dominated regime (the neutral phase). Simulations and analytic arguments show that the niche phase is favored in communities with large population sizes and relatively constant environments, whereas the neutral phase is favored in communities with small population sizes and fluctuating environments. Our results demonstrate how apparently neutral populations may arise even in communities inhabited by species with varying traits. PMID:25157131

Removal and recovery of mercury(II) from hazardous wastes using 1-(2-thiazolylazo)-2-naphthol functionalized activated carbon as solid phase extractant.

PubMed

Starvin, A M; Rao, T Prasada

2004-09-10

As a part of removal of toxic heavy metals from hazardous wastes, solid phase extraction (SPE) of mercury(II) at trace and ultra trace levels was studied using 1-(2-thiazolylazo)-2-naphthol (TAN) functionalized activated carbon (AC). The SPE material removes traces of mercury(II) quantitatively in the pH range 6.0 +/- 0.2. Other parameters that influence quantitative recovery of mercury(II), viz. percent concentration of TAN in AC, amount of TAN-AC, preconcentration time and volume of aqueous phase were varied and optimized. The possible means of removal of Hg(II) from other metal ions that are likely to be present in the wastes of the chloroalkali industry is discussed. The potential of TAN-functionalized AC SPE material for decontaminating mercury from the brine sludge and cell house effluent of a chloralkali plant has been evaluated.

Failed reciprocity in close social relationships and health: findings from the Whitehall II study.

PubMed

Chandola, Tarani; Marmot, Michael; Siegrist, Johannes

2007-10-01

To extend the model of effort-reward imbalance at work to close and more general social relationships and test the associations with different measures of health. Lack of reciprocity at work is associated with poorer health in a number of studies. However, few studies have analysed the effect of nonreciprocity in other kinds of social relationships on health. The Whitehall II Study is an ongoing prospective study of British civil servants (n=10308 at baseline in 1985-88). Cross-sectional data from the latest phase (7, n=6944 in 2002-04) were used in the analyses. The main exposure was a questionnaire measuring nonreciprocal social relations in partnership, parent-children, and general trusting relationships. Health measures included the SF-36 mental and physical component scores, General Health Questionnaire-30 depression subscale, Jenkins' Sleep disturbance questionnaire, and the Rose Angina questionnaire. Logistic and linear regression models were analysed, adjusted for potential confounders, and mediators of the association. Lack of reciprocity is associated with all measures of poorer health. This association attenuates after adjustment for previous health and additional confounders and mediators but remains significant in a majority of models. Negative social support from a close person is independently associated with reduced health, but adjusting for this effect does not eliminate the association of nonreciprocity with poor health. The effort-reward imbalance at work model has been extended to close and more general social relationships. Lack of reciprocity in partnership, parent-children and general trusting relationships is associated with poorer health.

Caltrans WeatherShare Phase II System: An Application of Systems and Software Engineering Process to Project Development

DOT National Transportation Integrated Search

2009-08-25

In cooperation with the California Department of Transportation, Montana State University's Western Transportation Institute has developed the WeatherShare Phase II system by applying Systems Engineering and Software Engineering processes. The system...

Roadway lighting and safety : phase II--monitoring quality, durability and efficiency.

DOT National Transportation Integrated Search

2011-10-01

This Phase II project follows a previous project titled Strategies to Address Nighttime Crashes at Rural, Unsignalized Intersections. Based on the results of the previous study, the Iowa Highway Research Board (IHRB) indicated interest in pursuing fu...

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...

Final report of evaluation of masonry coatings : phase II.

DOT National Transportation Integrated Search

1972-11-01

This research project was undertaken to evaluate several coating systems for concrete masonry to replace the presently used Class 2 rubbed finish. This is the report of Phase II, the field evaluation, of that project. : In early October 1970, applica...

Evaluation of Phase II of the SmarTraveler advanced traveler information system : operational test

DOT National Transportation Integrated Search

1994-07-31

Under contract to the Massachusetts Highway Department, the Central Transportation : Planning Staff (technical staff to the Boston MPO) chose Multisystems, Inc. of : Cambridge, Massachusetts, to perform an evaluation of Phase II of the SmarTraveler :...

System design and architecture for the IDTO prototype : phase II demonstration site (central Florida).

DOT National Transportation Integrated Search

2015-05-01

This report documents the System Design and Architecture for the Phase II implementation of the Integrated Dynamic Transit Operations (IDTO) Prototype bundle within the Dynamic Mobility Applications (DMA) portion of the Connected Vehicle Program. Thi...

Research safety vehicle. Phase II. Volume II. comprehensive technical results. Final report July 1975--December 1976

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

DiNapoli, N.; Fitzpatrick, M.; Strother, C.

1977-11-01

Phase I identified trends leading to the desired national social goals of the mid-1980's in vehicle crashworthiness, crash avoidance, damageability, pedestrian safety, fuel economy, emissions and cost, and characterized an RSV to satisfy them. In Phase II an RSV prototype was designed, developed and tested to demonstrate the feasibility of meeting these goals simultaneously. Although further refinement is necessary to assure operational validity, in all categories the results meet or exceed the most advanced performance specified by The Presidential Task Force on Motor Vehicle Goals beyond 1980.

Portable microfluidic platform for real-time, high sensitive detection and identification of trichloroethylene and other organochloride compounds

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

Jensen, Erik

In this successful SBIR Phase II effort, HJ Science & Technology, Inc. has designed and built a novel portable instrument capable of performing automated aqueous organochloride (chlorinated solvent) speciation analysis for environmental monitoring at DoE sites. Our technique employs performing organochloride conjugation, labeling the conjugate with an efficient fluorophore, and performing on-chip capillary electrophoresis separation with laser induced fluorescence detection. The key component of the portable instrument is a novel microfluidic chip capable of complete “end-to-end” automation of sample preparation, conjugation, labeling, and μCE separation and detection. In addition, the Phase II prototype includes key supporting instrumentation such as themore » optical module, pneumatic manifold, electronics, software, etc. As such, we have achieved all of the following 4 Phase II technical objectives: 1) Further refine and optimize the “on-chip” automation of the organochloride conjugation and labeling protocol, 2) Further improve the microfluidic chip fabrication process and the pneumatic manifold design in order to address issues related to performance consistency, product yield, performance reliability, and user friendliness, 3) Design and build the supporting components of the Phase II prototype including optical module, electronics, and software, and 4) Assemble the Phase II prototype hardware.« less

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

Brominated flame retardants in Chinese air before and after the phase out of polybrominated diphenyl ethers

NASA Astrophysics Data System (ADS)

Li, Wen-Long; Qi, Hong; Ma, Wan-Li; Liu, Li-Yan; Zhang, Zhi; Mohammed, Mohammed O. A.; Song, Wei-Wei; Zhang, Zifeng; Li, Yi-Fan

2015-09-01

Brominated flame retardants (BFRs), including polybrominated diphenyl ethers (PBDEs) and novel non-BDE flame retardants (NBFRs), were analyzed in Chinese air during China's POPs Soil and Air Monitoring Program Phase I (SAMP-I) and Phase II (SAMP-II). The levels of Σ12PBDEs and Σ6NBFRs in urban sites were significantly higher than those in rural sites and background sites. The higher detection rate and concentrations of high molecular weight PBDEs and NBFRs in Phase II indicated the changing of the commercial pattern of BFRs after the phase out of PBDEs in China. Temperature was the major factor affecting the seasonal variations of molecular weight BFRs in atmosphere. A significant correlation between BFRs concentration and gross domestic product (GDP) was observed, with the GDP parameter explained 59.4% and 72.7% of the total variability for Octa-BDEs and low molecular weight NBFRs, respectively. Our findings indicated an evolving commercial usage of BFRs from SAMP-I to SAMP-II, i.e. shifting from lower molecular weight to higher molecular weight congeners in China.

Understanding decomposition and encapsulation energies of structure I and II clathrate hydrates

NASA Astrophysics Data System (ADS)

Alavi, Saman; Ohmura, Ryo

2016-10-01

When compressed with water or ice under high pressure and low temperature conditions, some gases form solid gas hydrate inclusion compounds which have higher melting points than ice under those pressures. In this work, we study the balance of the guest-water and water-water interaction energies that lead to the formation of the clathrate hydrate phases. In particular, molecular dynamics simulations with accurate water potentials are used to study the energetics of the formation of structure I (sI) and II (sII) clathrate hydrates of methane, ethane, and propane. The dissociation enthalpy of the clathrate hydrate phases, the encapsulation enthalpy of methane, ethane, and propane guests in the corresponding phases, and the average bonding enthalpy of water molecules are calculated and compared with accurate calorimetric measurements and previous classical and quantum mechanical calculations, when available. The encapsulation energies of methane, ethane, and propane guests stabilize the small and large sI and sII hydrate cages, with the larger molecules giving larger encapsulation energies. The average water-water interactions are weakened in the sI and sII phases compared to ice. The relative magnitudes of the van der Waals potential energy in ice and the hydrate phases are similar, but in the ice phase, the electrostatic interactions are stronger. The stabilizing guest-water "hydrophobic" interactions compensate for the weaker water-water interactions and stabilize the hydrate phases. A number of common assumptions regarding the guest-cage water interactions are used in the van der Waals-Platteeuw statistical mechanical theory to predict the clathrate hydrate phase stability under different pressure-temperature conditions. The present calculations show that some of these assumptions may not accurately reflect the physical nature of the interactions between guest molecules and the lattice waters.

Understanding decomposition and encapsulation energies of structure I and II clathrate hydrates.

PubMed

Alavi, Saman; Ohmura, Ryo

2016-10-21

When compressed with water or ice under high pressure and low temperature conditions, some gases form solid gas hydrate inclusion compounds which have higher melting points than ice under those pressures. In this work, we study the balance of the guest-water and water-water interaction energies that lead to the formation of the clathrate hydrate phases. In particular, molecular dynamics simulations with accurate water potentials are used to study the energetics of the formation of structure I (sI) and II (sII) clathrate hydrates of methane, ethane, and propane. The dissociation enthalpy of the clathrate hydrate phases, the encapsulation enthalpy of methane, ethane, and propane guests in the corresponding phases, and the average bonding enthalpy of water molecules are calculated and compared with accurate calorimetric measurements and previous classical and quantum mechanical calculations, when available. The encapsulation energies of methane, ethane, and propane guests stabilize the small and large sI and sII hydrate cages, with the larger molecules giving larger encapsulation energies. The average water-water interactions are weakened in the sI and sII phases compared to ice. The relative magnitudes of the van der Waals potential energy in ice and the hydrate phases are similar, but in the ice phase, the electrostatic interactions are stronger. The stabilizing guest-water "hydrophobic" interactions compensate for the weaker water-water interactions and stabilize the hydrate phases. A number of common assumptions regarding the guest-cage water interactions are used in the van der Waals-Platteeuw statistical mechanical theory to predict the clathrate hydrate phase stability under different pressure-temperature conditions. The present calculations show that some of these assumptions may not accurately reflect the physical nature of the interactions between guest molecules and the lattice waters.

Phase I, open-cycle absorption solar cooling. Part IV. Executive summary analysis and resolution of critical issues and recommendations for Phase II. Final report

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

Wood, B.D.

The objective of this project is to advance lower cost solar cooling technology with the feasibility analysis, design and evaluation of proof-of-concept open cycle solar cooling concepts. The work is divided into three phases, with planned completion of each phase before proceeding with the following phase: Phase I - performance/economic/environmental related analysis and exploratory studies; Phase II - design and construction of an experimental system, including evaluative testing; Phase III - extended system testing during operation and engineering modifications as required. For Phase I, analysis and resolution of critical issues were completed with the objective of developing design specifications formore » an improved prototype OCA system.« less

Evaluation of hydrothermal resources of North Dakota. Phase II. Final technical report

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

Harris, K.L.; Howell, F.L.; Winczewski, L.M.

1981-06-01

This evaluation of the hydrothermal resources of North Dakota is based on existing data on file with the North Dakota Geological Survey (NDGS) and other state and federal agencies, and field and laboratory studies conducted. The principal sources of data used during the Phase II study were WELLFILE, the computer library of oil and gas well data developed during the Phase I study, and WATERCAT, a computer library system of water well data assembled during the Phase II study. A field survey of the shallow geothermal gradients present in selected groundwater observation holes was conducted. Laboratory determinations of the thermalmore » conductivity of core samples is being done to facilitate heat-flow calculations on those hole-of-convenience cased.« less

Effects of extracellular polymeric substances on the bioaccumulation of mercury and its toxicity toward the cyanobacterium Microcystis aeruginosa.

PubMed

Chen, Ho-Wen; Huang, Winn-Jung; Wu, Ting-Hsiang; Hon, Chen-Lin

2014-01-01

This investigation examines how extracellular polymeric substances (EPSs) and environmental factors affect the bioaccumulation and toxicity of inorganic mercury (+2 oxidation state, Hg(II)) using a culture of Microcystis aeruginosa, which dominates eutrophic reservoir populations. The identified EPSs were classified as carbohydrates and proteins. Evaluation of the bioaccumulation of Hg(II) in cells by multiple regression analysis reveals that the concentration of EPSs in filtrate, the initial concentration of Hg(II) in medium, and the culture age significantly affected the amount of Hg(II) accumulated. Composition profiles revealed that the concentrations of soluble carbohydrates were significantly higher in Hg(II)-accumulated cells than in the control ones. Preliminary results based on scanning electron microscopic (SEM) map investigations suggest that most of the Hg(II) was accumulated in the cytoplasm (intracellular). Additionally, the effective concentrations (EC50) of Hg(II) that inhibit the growth of M. aeruginosa were 38.6 μg L(-1) in the logarithmic phase and 17.5 μg L(-1) in the stationary phase. As expected, the production of more EPSs in the logarithmic phase typically implies higher EC50 values because EPSs may be regarded as a protective barrier of cells against an external Hg(II) load, enabling them to be less influenced by Hg(II).

Review article: novel oral-targeted therapies in inflammatory bowel disease.

PubMed

White, J R; Phillips, F; Monaghan, T; Fateen, W; Samuel, S; Ghosh, S; Moran, G W

2018-06-01

There is a great unmet clinical need for efficacious, tolerable, economical and orally administrated drugs for the treatment of inflammatory bowel disease (IBD). New therapeutic avenues have become possible including the development of medications that target specific genetic pathways found to be relevant in other immune mediated diseases. To provide an overview of recent clinical trials for new generation oral targeted medications that may have a future role in IBD management. Pubmed and Medline searches were performed up to 1 March 2018 using keywords: "IBD", "UC", "CD", "inflammatory bowel disease" "ulcerative colitis", "Crohn's disease" in combination with "phase", "study", "trial" and "oral". A manual search of the clinical trial register, article reference lists, abstracts from meetings of Digestive Disease Week, United European Gastroenterology Week and ECCO congress were also conducted. In randomised controlled trials primary efficacy endpoints were met for tofacitinib (JAK 1/3 inhibitor-phase III), upadacitinib (JAK 1 inhibitor-phase II) and AJM300 (α4-integrin antagonist-phase II) in ulcerative colitis. Ozanimod (S1P receptor agonist-phase II) also demonstrated clinical remission. For Crohn's disease, filgotinib (JAK1 inhibitor-phase II) met primary endpoints and laquinimod (quinolone-3-carboxide small molecule-phase II) was also efficacious. Trials using mongersen (SMAD7 inhibitor) and vidofludimus (dihydroorotate dehydrogenase inhibitor) have been halted. This is potentially the start of an exciting new era in which multiple therapeutic options are at the disposal of physicians to treat IBD on an individualised basis. Head-to-head studies with existing treatments and longer term safety data are needed for this to be possible. © 2018 John Wiley & Sons Ltd.

Avelumab: a new standard for treating metastatic Merkel cell carcinoma.

PubMed

Baker, Mairead; Cordes, Lisa; Brownell, Isaac

2018-04-01

Merkel cell carcinoma (MCC) is a rare and aggressive skin cancer. Although MCC is chemosensitive, responses to traditional chemotherapeutic agents are not durable. Avelumab, a novel anti-PD-L1 immune checkpoint inhibitor, recently became the first FDA-approved agent for the treatment of metastatic MCC and represents a new option to improve patient survival. Areas covered: This article presents an overview of MCC and summarizes the development of avelumab in the treatment of metastatic MCC. Preclinical studies, phase 1 and phase 2 clinical trials, and the safety profile of avelumab are reviewed. Future perspectives and ongoing studies are also discussed. Expert commentary: Avelumab demonstrated rapid and durable responses and a manageable safety profile in the treatment of metastatic MCC. Patient outcomes are favorable when compared to historical responses to standard chemotherapy. Ongoing clinical trials will continue to characterize avelumab and its optimal use in MCC therapy.

The hydrogen technology assessment, phase 1

NASA Technical Reports Server (NTRS)

Bain, Addison

1991-01-01

The purpose of this phase 1 report is to begin to form the information base of the economics and energy uses of hydrogen-related technologies on which the members of the National Hydrogen Association (NHA) can build a hydrogen vision of the future. The secondary goal of this report is the development of NHA positions on national research, development, and demonstration opportunities. The third goal, with the aid of the established hydrogen vision and NHA positions, is to evaluate ongoing federal research goals and activities. The evaluations will be performed in a manner that compares the costs associated with using systems that achieve those goals against the cost of performing those tasks today with fossil fuels. From this ongoing activity should emerge an NHA information base, one or more hydrogen visions of the future, and cost and performance targets for hydrogen applications to complete in the market place.

Distinction between added-energy and phase-resetting mechanisms in non-invasively detected somatosensory evoked responses.

PubMed

Fedele, T; Scheer, H-J; Burghoff, M; Waterstraat, G; Nikulin, V V; Curio, G

2013-01-01

Non-invasively recorded averaged event-related potentials (ERP) represent a convenient opportunity to investigate human brain perceptive and cognitive processes. Nevertheless, generative ERP mechanisms are still debated. Two previous approaches have been contested in the past: the added-energy model in which the response raises independently from the ongoing background activity, and the phase-reset model, based on stimulus-driven synchronization of oscillatory ongoing activity. Many criteria for the distinction of these two models have been proposed, but there is no definitive methodology to disentangle them, owing also to the limited information at the single trial level. Here, we propose a new approach combining low-noise EEG technology and multivariate decomposition techniques. We present theoretical analyses based on simulated data and identify in high-frequency somatosensory evoked responses an optimal target for the distinction between the two mechanisms.

75 FR 62530 - Eagle Creek Hydro Power, LLC; Laredo Ridge Wind, LLC; RRI Energy West, Inc.; Goshen Phase II LLC...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-10-12

...; EG10-52-000; EG10-53-000; EG10- 54-000; EG10-55-000; EG10-56-000] Eagle Creek Hydro Power, LLC; Laredo Ridge Wind, LLC; RRI Energy West, Inc.; Goshen Phase II LLC; Solar Partners I, LLC; Solar Partners II, LLC; Solar Partners VIII, LLC; Notice of Effectiveness of Exempt Wholesale Generator Status October 1...

Project 1946: Phase II

DTIC Science & Technology

2010-07-01

History (Project 1946 - Phase II),” for the National Intelligence Council. The views, opinions, and findings should not be construed as representing...29 Section 1: Senior Leadership  Foreign Assistance  Officer Corps  Saddam‘s Personality ...45 Section 3: Personal Interactions with Saddam  Senior Leadership

Magnetic sensor for nondestructive evaluation of deteriorated prestressing strand : phase II.

DOT National Transportation Integrated Search

2011-08-01

This report gives an account of the execution and achievements in Phase II of the project completed through August 2011. The main objective of this project is to advance the practical development of a nondestructive testing and evaluation method usin...

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. |

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.

Expendable Air Vehicles/High Altitude Balloon Technology. Phase 1.

DTIC Science & Technology

1991-08-02

CHR/91 -2750 I I I I I THIS PAGE INTENTIONALLY LEFT BLANK 3 I I U I I I I I I I I I CHR/91 -2750 PREFACE The work described in this Phase II SBIR...Final Technical Report is the implementation of a capability which Coleman Research Corporation demon- strated during a Phase I SBIR (contract number...CRC) has developed a Balloon Drift Pattern Simulation 1BDPS). CRC developed this simulation software for digital computers as a product of a Phase II

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.

The Design of Phase II Clinical Trials Testing Cancer Therapeutics: Consensus Recommendations from the Clinical Trial Design Task Force of the National Cancer Institute Investigational Drug Steering Committee

PubMed Central

Seymour, Lesley; Ivy, S. Percy; Sargent, Daniel; Spriggs, David; Baker, Laurence; Rubinstein, Larry; Ratain, Mark J; Le Blanc, Michael; Stewart, David; Crowley, John; Groshen, Susan; Humphrey, Jeffrey S; West, Pamela; Berry, Donald

2010-01-01

The optimal design of phase II studies continues to be the subject of vigorous debate, especially with regards to studies of newer molecularly targeted agents. The observations that many new therapeutics ‘fail’ in definitive phase III studies, coupled with the numbers of new agents to be tested as well as the increasing costs and complexity of clinical trials further emphasizes the critical importance of robust and efficient phase II design. The Clinical Trial Design Task Force(CTD-TF)of the NCI Investigational Drug Steering Committee (IDSC) has published a series of discussion papers on Phase II trial design in Clinical Cancer Research. The IDSC has developed formal recommendations regarding aspects of phase II trial design which are the subject of frequent debate such as endpoints(response vs. progression free survival), randomization(single arm designs vs. randomization), inclusion of biomarkers, biomarker based patient enrichment strategies, and statistical design(e.g. two stage designs vs. multiple-group adaptive designs). While these recommendations in general encourage the use of progression-free survival as the primary endpoint, the use of randomization, the inclusion of biomarkers and the incorporation of newer designs, we acknowledge that objective response as an endpoint, and single arm designs, remain relevant in certain situations. The design of any clinical trial should always be carefully evaluated and justified based on the characteristic specific to the situation. PMID:20215557

Effects of phase II cardiac rehabilitation on job stress and health-related quality of life after return to work in middle-aged patients with acute myocardial infarction.

PubMed

Yonezawa, Ryusuke; Masuda, Takashi; Matsunaga, Atsuhiko; Takahashi, Yumi; Saitoh, Masakazu; Ishii, Akira; Kutsuna, Toshiki; Matsumoto, Takuya; Yamamoto, Kazuya; Aiba, Naoko; Hara, Miyako; Izumi, Tohru

2009-05-01

The aim of the present study was to clarify the effects of phase II cardiac rehabilitation (CR) on job stress and health-related quality of life (HRQOL) after return to work in middle-aged patients with acute myocardial infarction (AMI). A total of 109 middle-aged outpatients (57 +/- 7 years) who completed a phase I CR program after AMI were enrolled, 72 of whom participated in a phase II CR program for 5 months after hospital discharge (CR group) and 37 who discontinued the phase II CR program after the discharge (non-CR group). Job stress was assessed at 6 months after the AMI using a brief job stress questionnaire containing questions related to job stressors, worksite support, level of satisfaction with work or daily life, and psychological distress. HRQOL was assessed using the short-form 36-item health survey (SF-36) at hospital discharge and at 3 and 6 months after the AMI. There were no significant differences in clinical and occupational characteristics between the CR and non-CR groups. The CR group patients exhibited significantly better results for job stressors and psychological distress and higher SF-36 scores at 6 months after the AMI, as compared with those in the non-CR group. These findings suggest that discontinuing a phase II CR program induced chronic psychosocial stress after return to work in these middle-aged post-AMI patients.

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.

Elastic properties of crystalline and liquid gallium at high pressures

NASA Astrophysics Data System (ADS)

Lyapin, A. G.; Gromnitskaya, E. L.; Yagafarov, O. F.; Stal'Gorova, O. V.; Brazhkin, V. V.

2008-11-01

The elastic properties of gallium, such as the bulk modulus B, the shear modulus G, and the Poisson’s ratio σ, are investigated and the relative change in the volume is determined in the stability regions of the Ga I, Ga II, and liquid phases at pressures of up to 1.7 GPa. The observed lines of the Ga I-Ga II phase transition and the melting curves of the Ga I and Ga II phases are in good agreement with the known phase diagram of gallium; in this case, the coordinates of the Ga I-Ga II-melt triple point are determined to be 1.24 ± 0.40 GPa and 277 ± 2 K. It is shown that the Ga I-Ga II phase transition is accompanied by a considerable decrease in the moduli B (by 30%) and G (by 55%) and an increase in the density by 5.7%. The Poisson’s ratio exhibits a jump from typically covalent values of approximately 0.22-0.25 to values of approximately 0.32-0.33, which are characteristic of metals. The observed behavior of the elastic characteristics is described in the framework of the model of the phase transition from a “quasi-molecular” (partially covalent) metal state to a “normal” metal state. An increase in the Poisson’s ratio in the Ga I phase from 0.22 to 0.25 with an increase in the pressure can be interpreted as a decrease in the degree of covalence, i.e., the degree of spatial anisotropy of the electron density along the bonds, whereas the large value of the pressure derivative of the bulk modulus (equal to approximately 8) observed up to the transition to the Ga II phase or the melt is associated not only with the quasicovalent nature of the Ga I phase but also with the structural features. In view of the presence of seven neighbors for each gallium atom in the Ga I phase, the gallium lattice can be treated as a structure intermediate between typical open-packed and close-packed structures. Premelting effects, such as a flattening of the isothermal dependence of the shear modulus G( p) with increasing pressure and an increase in the slope of the isobaric dependences G( T) with increasing temperature, are revealed in the vicinity of the melting curve. The bulk modulus of liquid gallium near the melting curve proves to be rather close to the corresponding values for the normal metal Ga II.

Project NOAH: Regulating modern sea-level rise. Phase II: Jerusalem Underground

NASA Astrophysics Data System (ADS)

Newman, Walter S.; Fairbridge, Rhodes W.

This proposal builds a high-speed inter-urban express between Jerusalem and Tel Aviv, generates 1500 megawatts of hydroelectric energy, curtails littoral erosion, builds a port along the Israeli Mediterranean coast and demands peaceful cooperation on both sides of the Jordan River. Phase II represents a pilot project demonstrating the feasibility of continuing to regulate world sea-level by a new series of water regulation schemes. Phase I previously described all those projects already completed or underway which have inadvertently and/or unintentionally served the purpose of sea-level regulation. These forms of Phase I sea-level regulation include large and small reservoirs, irrigation projects, water infiltration schemes, farm ponds, and swimming and reflecting pools. All these water storage projects have already exercised a very appreciable brake on 20th century sea-level rise. Phase II outlines a high-visibility proposal which will serve to illustrate the viability of “Project NOAH”.

Characterization of pH dependent Mn(II) oxidation strategies and formation of a bixbyite-like phase by Mesorhizobium australicum T-G1

PubMed Central

Bohu, Tsing; Santelli, Cara M.; Akob, Denise M.; Neu, Thomas R.; Ciobota, Valerian; Rösch, Petra; Popp, Jürgen; Nietzsche, Sándor; Küsel, Kirsten

2015-01-01

Despite the ubiquity of Mn oxides in natural environments, there are only a few observations of biological Mn(II) oxidation at pH < 6. The lack of low pH Mn-oxidizing bacteria (MOB) isolates limits our understanding of how pH influences biological Mn(II) oxidation in extreme environments. Here, we report that a novel MOB isolate, Mesorhizobium australicum strain T-G1, isolated from an acidic and metalliferous uranium mining area, can oxidize Mn(II) at both acidic and neutral pH using different enzymatic pathways. X-ray diffraction, Raman spectroscopy, and scanning electron microscopy with energy dispersive X-ray spectroscopy revealed that T-G1 initiated bixbyite-like Mn oxide formation at pH 5.5 which coincided with multi-copper oxidase expression from early exponential phase to late stationary phase. In contrast, reactive oxygen species (ROS), particularly superoxide, appeared to be more important for T-G1 mediated Mn(II) oxidation at neutral pH. ROS was produced in parallel with the occurrence of Mn(II) oxidation at pH 7.2 from early stationary phase. Solid phase Mn oxides did not precipitate, which is consistent with the presence of a high amount of H2O2 and lower activity of catalase in the liquid culture at pH 7.2. Our results show that M. australicum T-G1, an acid tolerant MOB, can initiate Mn(II) oxidation by varying its oxidation mechanisms depending on the pH and may play an important role in low pH manganese biogeochemical cycling. PMID:26236307

Life cycle and economic efficiency analysis phase II : durable pavement markings.

DOT National Transportation Integrated Search

2011-04-01

This report details the Phase II analysis of the life cycle and economic efficiency of inlaid tape : and thermoplastic. Waterborne paint was included as a non-durable for comparison purposes : only. In order to find the most economical product for sp...

77 FR 19660 - Combined Notice of Filings #1

Federal Register 2010, 2011, 2012, 2013, 2014

2012-04-02

.... Applicants: Goshen Phase II LLC, Ridgeline Alternative Energy, LLC. Description: Joint Application for Authorization under Section 203 of the Federal Power Act of Goshen Phase II and Ridgeline Alternative Energy... DEPARTMENT OF ENERGY Federal Energy Regulatory Commission Combined Notice of Filings 1 Take notice...

Field testing of hand-held infrared thermography, phase II TPF-5(247) : final report.

DOT National Transportation Integrated Search

2016-05-01

This report is the second of two volumes that document results from the pooled fund study TPF-5 (247), Development of : Handheld Infrared Thermography, Phase II. The interim report (volume I) studied the implementation of handheld thermography : by p...

Reassessing Phase II Heart Failure Clinical Trials: Consensus Recommendations

PubMed Central

Butler, Javed; Hamo, Carine E.; Udelson, James E.; O’Connor, Christopher; Sabbah, Hani N.; Metra, Marco; Shah, Sanjiv J.; Kitzman, Dalane W.; Teerlink, John; Bernstein, Harold S.; Brooks, Gabriel; Depre, Christophe; DeSouza, Mary M.; Dinh, Wilfried; Donovan, Mark; Frische-Danielson, Regina; Frost, Robert J.; Garza, Dahlia; Gohring, Udo-Michael; Hellawell, Jennifer; Hsia, Judith; Ishihara, Shiro; Kay-Mugford, Patricia; Koglin, Joerg; Kozinn, Marc; Larson, Christopher J.; Mayo, Martha; Gan, Li-Ming; Mugnier, Pierrre; Mushonga, Sekayi; Roessig, Lothar; Russo, Cesare; Salsali, Afshin; Satler, Carol; Shi, Victor; Ticho, Barry; van der Laan, Michael; Yancy, Clyde; Stockbridge, Norman; Gheorghiade, Mihai

2017-01-01

The increasing burden and the continued suboptimal outcomes for patients with heart failure underlines the importance of continued research to develop novel therapeutics for this disorder. This can only be accomplished with successful translation of basic science discoveries into direct human application through effective clinical trial design and execution that results in a substantially improved clinical course and outcomes. In this respect, phase II clinical trials play a pivotal role in determining which of the multitude of potential basic science discoveries should move to the large and expansive registration trials in humans. A critical examination of the phase II trials in heart failure reveals multiple shortcomings in their concept, design, execution, and interpretation. To further a dialogue regarding the challenges and potential for improvement and the role of phase II trials in patients with heart failure, the Food and Drug Administration facilitated a meeting on October 17th 2016 represented by clinicians, researchers, industry members, and regulators. This document summarizes the discussion from this meeting and provides key recommendations for future directions. PMID:28356300

Malignant pleural mesothelioma: a phase II trial with docetaxel.

PubMed

Vorobiof, D A; Rapoport, B L; Chasen, M R; Abratt, R P; Cronje, N; Fourie, L; McMichael, G; Hacking, D

2002-03-01

Current cytotoxic therapy has been of limited benefit to patients with malignant pleural mesothelioma. Single agent chemotherapy has been extensively evaluated in small series of phase II clinical trials, with disappointing responses. Docetaxel, an effective taxane in the treatment of advanced breast cancer and non-small-cell lung cancer, was administered intravenously at a dose of 100 mg/m2 every 3 weeks to 30 chemotherapy naive patients with malignant pleural mesothelioma in a prospective multi-institutional phase II clinical trial. An objective response rate (partial responses) of 10% was documented. Additionally, 21% of the patients had minor responses (intention-to-treat analysis). Three patients died within 2 weeks post-first cycle of therapy, although only one patient's death was directly attributed to the investigational drug, whilst in the majority of the patients, manageable and treatable toxicities were encountered. In this phase II clinical trial, docetaxel proved to be mildly effective in the treatment of patients with malignant pleural mesothelioma.

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.

Optical constants of solid methane and ethane from 10,000 to 450/cm. [in outer planets atmospheres

NASA Technical Reports Server (NTRS)

Pearl, J.; Ngoh, M.; Ospina, M.; Khanna, R.

1991-01-01

Near- and mid-IR spectra of thin films of crystalling phase I and phase II C2H6 are presented using a combined least squares and Kramers-Kronig analysis. Complex refractive indices derived from these data are also presented. To obtain material in phase I, samples are annealed at 33 K for about 30 min; phase II is obtained by recooling below the transition temperature of 20.4 K. The derived optical parameters are shown. The infrared spectrum of phase I CH4 exhibits broad structureless absorptions at about 1300 and 2600/cm. On cooling the sample below 20.4 K (phase II), the absorptions are sharpened, and each band develops fine structure. The present results and those of Roux et al. (1979) are compared. The agreement with the real parts is found to be excellent; given the difference in resolution, the agreement with the imaginary parts is also good.

Nitrous oxide emissions in a membrane bioreactor treating saline wastewater contaminated by hydrocarbons.

PubMed

Mannina, Giorgio; Cosenza, Alida; Di Trapani, Daniele; Laudicina, Vito Armando; Morici, Claudia; Ødegaard, Hallvard

2016-11-01

The joint effect of wastewater salinity and hydrocarbons on nitrous oxide emission was investigated. The membrane bioreactor pilot plant was operated with two phases: i. biomass acclimation by increasing salinity from 10gNaClL(-1) to 20gNaClL(-1) (Phase I); ii. hydrocarbons dosing at 20mgL(-1) with a constant salt concentration of 20gNaClL(-1) (Phase II). The Phase I revealed a relationship between nitrous oxide emissions and salinity. During the end of the Phase I, the activity of nitrifiers started to recover, indicating a partial acclimatization. During the Phase II, the hydrocarbon shock induced a temporary inhibition of the biomass with the suppression of nitrous oxide emissions. The results revealed that the oxic tank was the major source of nitrous oxide emission, likely due to the gas stripping by aeration. The joint effect of salinity and hydrocarbons was found to be crucial for the production of nitrous oxide. Copyright © 2016 Elsevier Ltd. All rights reserved.

Peripheral and central immune cell reservoirs in tissues from asymptomatic cats chronically infected with feline immunodeficiency virus.

PubMed

Eckstrand, C D; Sparger, E E; Pitt, K A; Murphy, B G

2017-01-01

Feline immunodeficiency virus (FIV) infection in cats results in life-long viral persistence and progressive immunopathology. We have previously described a cohort of experimentally infected cats demonstrating a progressive decline of peripheral blood CD4+ T-cell over six years in the face of apparent peripheral viral latency. More recently we reported findings from this same cohort that revealed popliteal lymph node tissue as sites for ongoing viral replication suggesting that tissue reservoirs are important in FIV immunopathogenesis during the late asymptomatic phase of infection. Results reported herein characterize important tissue reservoirs of active viral replication during the late asymptomatic phase by examining biopsied specimens of spleen, mesenteric lymph node (MLN), and intestine from FIV-infected and uninfected control cats. Peripheral blood collected coincident with harvest of tissues demonstrated severe CD4+ T-cell depletion, undetectable plasma viral gag RNA and rarely detectable peripheral blood mononuclear cell (PBMC)-associated viral RNA (vRNA) by real-time PCR. However, vRNA was detectable in all three tissue sites from three of four FIV-infected cats despite the absence of detectable vRNA in plasma. A novel in situ hybridization assay identified B cell lymphoid follicular domains as microanatomical foci of ongoing FIV replication. Additionally, we demonstrated that CD4+ leukocyte depletion in tissues, and CD4+ and CD21+ leukocytes as important cellular reservoirs of ongoing replication. These findings revealed that tissue reservoirs support foci of ongoing viral replication, in spite of highly restricted viral replication in blood. Lentiviral eradication strategies will need address tissue viral reservoirs.

Peripheral and central immune cell reservoirs in tissues from asymptomatic cats chronically infected with feline immunodeficiency virus

PubMed Central

Sparger, E. E.; Pitt, K. A.

2017-01-01

Feline immunodeficiency virus (FIV) infection in cats results in life-long viral persistence and progressive immunopathology. We have previously described a cohort of experimentally infected cats demonstrating a progressive decline of peripheral blood CD4+ T-cell over six years in the face of apparent peripheral viral latency. More recently we reported findings from this same cohort that revealed popliteal lymph node tissue as sites for ongoing viral replication suggesting that tissue reservoirs are important in FIV immunopathogenesis during the late asymptomatic phase of infection. Results reported herein characterize important tissue reservoirs of active viral replication during the late asymptomatic phase by examining biopsied specimens of spleen, mesenteric lymph node (MLN), and intestine from FIV-infected and uninfected control cats. Peripheral blood collected coincident with harvest of tissues demonstrated severe CD4+ T-cell depletion, undetectable plasma viral gag RNA and rarely detectable peripheral blood mononuclear cell (PBMC)-associated viral RNA (vRNA) by real-time PCR. However, vRNA was detectable in all three tissue sites from three of four FIV-infected cats despite the absence of detectable vRNA in plasma. A novel in situ hybridization assay identified B cell lymphoid follicular domains as microanatomical foci of ongoing FIV replication. Additionally, we demonstrated that CD4+ leukocyte depletion in tissues, and CD4+ and CD21+ leukocytes as important cellular reservoirs of ongoing replication. These findings revealed that tissue reservoirs support foci of ongoing viral replication, in spite of highly restricted viral replication in blood. Lentiviral eradication strategies will need address tissue viral reservoirs. PMID:28384338

Distributed Attention Is Implemented through Theta-Rhythmic Gamma Modulation.

PubMed

Landau, Ayelet Nina; Schreyer, Helene Marianne; van Pelt, Stan; Fries, Pascal

2015-08-31

When subjects monitor a single location, visual target detection depends on the pre-target phase of an ∼8 Hz brain rhythm. When multiple locations are monitored, performance decrements suggest a division of the 8 Hz rhythm over the number of locations, indicating that different locations are sequentially sampled. Indeed, when subjects monitor two locations, performance benefits alternate at a 4 Hz rhythm. These performance alternations were revealed after a reset of attention to one location. Although resets are common and important events for attention, it is unknown whether, in the absence of resets, ongoing attention samples stimuli in alternation. Here, we examined whether spatially specific attentional sampling can be revealed by ongoing pre-target brain rhythms. Visually induced gamma-band activity plays a role in spatial attention. Therefore, we hypothesized that performance on two simultaneously monitored stimuli can be predicted by a 4 Hz modulation of gamma-band activity. Brain rhythms were assessed with magnetoencephalography (MEG) while subjects monitored bilateral grating stimuli for a unilateral target event. The corresponding contralateral gamma-band responses were subtracted from each other to isolate spatially selective, target-related fluctuations. The resulting lateralized gamma-band activity (LGA) showed opposite pre-target 4 Hz phases for detected versus missed targets. The 4 Hz phase of pre-target LGA accounted for a 14.5% modulation in performance. These findings suggest that spatial attention is a theta-rhythmic sampling process that is continuously ongoing, with each sampling cycle being implemented through gamma-band synchrony. Copyright © 2015 Elsevier Ltd. All rights reserved.

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.

NOx Emissions Characteristics and Correlation Equations of Two P and W's Axially Staged Sector Combustors Developed Under NASA Environmentally Responsible Aviation (ERA) Project

NASA Technical Reports Server (NTRS)

He, Zhuohui J.

2017-01-01

Two P&W (Pratt & Whitney)'s axially staged sector combustors have been developed under NASA's Environmentally Responsible Aviation (ERA) project. One combustor was developed under ERA Phase I, and the other was developed under ERA Phase II. Nitrogen oxides (NOx) emissions characteristics and correlation equations for these two sector combustors are reported in this article. The Phase I design was to optimize the NOx emissions reduction potential, while the Phase II design was more practical and robust. Multiple injection points and fuel staging strategies are used in the combustor design. Pilot-stage injectors are located on the front dome plate of the combustor, and main-stage injectors are positioned on the top and bottom (Phase I) or on the top only (Phase II) of the combustor liners downstream. Low power configuration uses only pilot-stage injectors. Main-stage injectors are added to high power configuration to help distribute fuel more evenly and achieve lean burn throughout the combustor yielding very low NOx emissions. The ICAO (International Civil Aviation Organization) landing-takeoff NOx emissions are verified to be 88 percent (Phase I) and 76 percent (Phase II) under the ICAO CAEP/6 (Committee on Aviation Environmental Protection 6th Meeting) standard, exceeding the ERA project goal of 75 percent reduction, and the combustors proved to have stable combustion with room to maneuver on fuel flow splits for operability.

Development of a Low Cost Molded Plastic Missile/RPV Control Surface Actuator

DTIC Science & Technology

1975-10-01

Glass Fiber 3 2.1.2.2 Nylon/30% Glaso Fiber 7 2.2 Phase I Testing Of Polyimide/Glass 8 j/ Burst Testsl 11tig 2.2.2atgu TechShatset S.2. Phse Cliner oldng...Dimensional and Hard- 23 a >~ ness Change Results19 2.2.4.2.3 Weight Changes 23 2.2.5 Phase II Environmental Testing 27 II I -ii TALIO ONET TABLE OF...CONTENTS (CONT’D) SECTION PAGE 2.3 Phase I Analysis and Design 27 2.3.1 Sizing and Optimizing AR 27 2.3.2 Valve Sizing 36 2.3.3 Pistons Side Load and Rocker

Minimizing the Maximum Expected Sample Size in Two-Stage Phase II Clinical Trials with Continuous Outcomes

PubMed Central

Wason, James M. S.; Mander, Adrian P.

2012-01-01

Two-stage designs are commonly used for Phase II trials. Optimal two-stage designs have the lowest expected sample size for a specific treatment effect, for example, the null value, but can perform poorly if the true treatment effect differs. Here we introduce a design for continuous treatment responses that minimizes the maximum expected sample size across all possible treatment effects. The proposed design performs well for a wider range of treatment effects and so is useful for Phase II trials. We compare the design to a previously used optimal design and show it has superior expected sample size properties. PMID:22651118

Nevada Test and Training Range Depleted Uranium Target Disposal Environmental Assessment

DTIC Science & Technology

2005-03-01

to establish the probability and scope of such transport. Long-Term Fate of Depleted Uranium at Aberdeen and Yuma Proving Grounds Phase II: Human...1990. Long-Term Fate of Depleted Uranium at Aberdeen and Yuma Proving Grounds Final Report, Phase 1: Geochemical Transport and Modeling. Los...of Depleted Uranium at Aberdeen and Yuma Proving Grounds , Phase II: Human Health and Ecological Risk Assessments. Los Alamos National Laboratory

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.

Lead(ii) soaps: crystal structures, polymorphism, and solid and liquid mesophases.

PubMed

Martínez-Casado, F J; Ramos-Riesco, M; Rodríguez-Cheda, J A; Redondo-Yélamos, M I; Garrido, L; Fernández-Martínez, A; García-Barriocanal, J; da Silva, I; Durán-Olivencia, M; Poulain, A

2017-07-05

The long-chain members of the lead(ii) alkanoate series or soaps, from octanoate to octadecanoate, have been thoroughly characterized by means of XRD, PDF analysis, DSC, FTIR, ssNMR and other techniques, in all their phases and mesophases. The crystal structures at room temperature of all of the members of the series are now solved, showing the existence of two polymorphic forms in the room temperature crystal phase, different to short and long-chain members. Only nonanoate and decanoate present both forms, and this polymorphism is proven to be monotropic. At higher temperature, these compounds present a solid mesophase, defined as rotator, a liquid crystal phase and a liquid phase, all of which have a similar local arrangement. Since some lead(ii) soaps appear as degradation compounds in oil paintings, the solved crystal structures of lead(ii) soaps can now be used as fingerprints for their detection using X-ray diffraction. Pair distribution function analysis on these compounds is very similar in the same phases and mesophases for the different members, showing the same short range order. This observation suggests that this technique could also be used in the detection of these compounds in disordered phases or in the initial stages of formation in paintings.

Transmissible cancers in an evolutionary context.

PubMed

Ujvari, Beata; Papenfuss, Anthony T; Belov, Katherine

2016-07-01

Cancer is an evolutionary and ecological process in which complex interactions between tumour cells and their environment share many similarities with organismal evolution. Tumour cells with highest adaptive potential have a selective advantage over less fit cells. Naturally occurring transmissible cancers provide an ideal model system for investigating the evolutionary arms race between cancer cells and their surrounding micro-environment and macro-environment. However, the evolutionary landscapes in which contagious cancers reside have not been subjected to comprehensive investigation. Here, we provide a multifocal analysis of transmissible tumour progression and discuss the selection forces that shape it. We demonstrate that transmissible cancers adapt to both their micro-environment and macro-environment, and evolutionary theories applied to organisms are also relevant to these unique diseases. The three naturally occurring transmissible cancers, canine transmissible venereal tumour (CTVT) and Tasmanian devil facial tumour disease (DFTD) and the recently discovered clam leukaemia, exhibit different evolutionary phases: (i) CTVT, the oldest naturally occurring cell line is remarkably stable; (ii) DFTD exhibits the signs of stepwise cancer evolution; and (iii) clam leukaemia shows genetic instability. While all three contagious cancers carry the signature of ongoing and fairly recent adaptations to selective forces, CTVT appears to have reached an evolutionary stalemate with its host, while DFTD and the clam leukaemia appear to be still at a more dynamic phase of their evolution. Parallel investigation of contagious cancer genomes and transcriptomes and of their micro-environment and macro-environment could shed light on the selective forces shaping tumour development at different time points: during the progressive phase and at the endpoint. A greater understanding of transmissible cancers from an evolutionary ecology perspective will provide novel avenues for the prevention and treatment of both contagious and non-communicable cancers. © 2016 The Authors. BioEssays published by WILEY Periodicals, Inc.

Magma extrusion during the Ubinas 2013–2014 eruptive crisis based on satellite thermal imaging (MIROVA) and ground-based monitoring

USGS Publications Warehouse

Coppola, Diego; Macedo, Orlando; Ramos, Domingo; Finizola, Anthony; Delle Donne, Dario; del Carpio, Jose; White, Randall A.; McCausland, Wendy; Centeno, Riky; Rivera, Marco; Apaza, Fredy; Ccallata, Beto; Chilo, Wilmer; Cigolini, Corrado; Laiolo, Marco; Lazarte, Ivonne; Machaca, Roger; Masias, Pablo; Ortega, Mayra; Puma, Nino; Taipe, Edú

2015-01-01

After 3 years of mild gases emissions, the Ubinas volcano entered in a new eruptive phase on September 2nd, 2013. The MIROVA system (a space-based volcanic hot-spot detection system), allowed us to detect in near real time the thermal emissions associated with the eruption and provided early evidence of magma extrusion within the deep summit crater. By combining IR data with plume height, sulfur emissions, hot spring temperatures and seismic activity, we interpret the thermal output detected over Ubinas in terms of extrusion rates associated to the eruption. We suggest that the 2013–2014 eruptive crisis can be subdivided into three main phases: (i) shallow magma intrusion inside the edifice, (ii) extrusion and growing of a lava plug at the bottom of the summit crater coupled with increasing explosive activity and finally, (iii) disruption of the lava plug and gradual decline of the explosive activity. The occurrence of the 8.2 Mw Iquique (Chile) earthquake (365 km away from Ubinas) on April 1st, 2014, may have perturbed most of the analyzed parameters, suggesting a prompt interaction with the ongoing volcanic activity. In particular, the analysis of thermal and seismic datasets shows that the earthquake may have promoted the most intense thermal and explosive phase that culminated in a major explosion on April 19th, 2014.These results reveal the efficiency of space-based thermal observations in detecting the extrusion of hot magma within deep volcanic craters and in tracking its evolution. We emphasize that, in combination with other geophysical and geochemical datasets, MIROVA is an essential tool for monitoring remote volcanoes with rather difficult accessibility, like those of the Andes that reach remarkably high altitudes.

Freeing Water from Viruses and Bacteria

NASA Technical Reports Server (NTRS)

2004-01-01

Four years ago, Argonide Corporation, a company focused on the research, production, and marketing of specialty nano materials, was seeking to develop applications for its NanoCeram[R] fibers. Only 2 nanometers in diameter, these nano aluminum oxide fibers possessed unusual bio-adhesive properties. When formulated into a filter material, the electropositive fibers attracted and retained electro-negative particles such as bacteria and viruses in water-based solutions. This technology caught the interest of NASA as a possible solution for improved water filtration in space cabins. NASA's Johnson Space Center awarded Sanford, Florida-based Argonide a Phase I Small Business Innovation Research (SBIR) contract to determine the feasibility of using the company's filter for purifying recycled space cabin water. Since viruses and bacteria can be carried aboard space cabins by space crews, the ability to detect and remove these harmful substances is a concern for NASA. The Space Agency also desired an improved filter to polish the effluent from condensed and waste water, producing potable drinking water. During its Phase I partnership with NASA, Argonide developed a laboratory-size filter capable of removing greater than 99.9999 percent of bacteria and viruses from water at flow rates more than 200 times faster than virus-rated membranes that remove particles by sieving. Since the new filter s pore size is rather large compared to other membranes, it is also less susceptible to clogging by small particles. In September 2002, Argonide began a Phase II SBIR project with Johnson to develop a full-size cartridge capable of serving a full space crew. This effort, which is still ongoing, enabled the company to demonstrate that its filter media is an efficient absorbent for DNA and RNA.

A Phase I Trial of High-Dose Lenalidomide and Melphalan as Conditioning for Autologous Stem Cell Transplantation in Relapsed or Refractory Multiple Myeloma.

PubMed

Mark, Tomer M; Guarneri, Danielle; Forsberg, Peter; Rossi, Adriana; Pearse, Roger; Perry, Arthur; Pekle, Karen; Tegnestam, Linda; Greenberg, June; Shore, Tsiporah; Gergis, Usama; Mayer, Sebastian; Van Besien, Koen; Ely, Scott; Jayabalan, David; Sherbenou, Daniel; Coleman, Morton; Niesvizky, Ruben

2017-06-01

Autologous stem cell transplantation (ASCT) conditioned with high-dose chemotherapy has long been established as the standard of care for eligible patients with newly diagnosed multiple myeloma. Despite recent therapeutic advances, high-dose melphalan (HDM) remains the chemotherapy regimen of choice in this setting. Lenalidomide (LEN) in combination with low-dose dexamethasone is recognized as a standard of care for patients with relapsed or refractory multiple myeloma (RRMM), and there is growing support for the administration of LEN as maintenance therapy post-ASCT. In view of the above, the present phase I clinical trial was designed to evaluate the safety and tolerability of high-dose LEN (HDLEN) in patients with RRMM, and to determine the maximum tolerated dose of HDLEN when added to HDM before ASCT. Despite administering HDLEN at doses of up to 350 mg/day, the maximum tolerated dose could not be determined, owing to an insufficient number of dose-limiting toxicities in the 21 patients enrolled in the trial. Conditioning with HDLEN plus HDM was associated with a favorable tolerability profile. Adverse events following ASCT were as expected with HDM. Median progression-free and overall survival were 10 months and 22 months, respectively, in this population of heavily pretreated patients. Our findings suggest that HDLEN in combination with HDM may offer significant potential as a conditioning regimen before ASCT in patients with RRMM. These preliminary findings are now being evaluated further in an ongoing phase II clinical trial. Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

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

Measurements of canine aqueous humor inflammatory mediators and the effect of carprofen following anterior chamber paracentesis.

PubMed

Pinard, Chantale L; Gauvin, Dominique; Moreau, Maxim; Martel-Pelletier, Johanne; Pelletier, Jean-Pierre; Troncy, Eric

2011-09-01

Phase I: To evaluate levels of prostaglandin E(2) (PGE(2) ), nitrites and nitrates (NO(x) ), tumor necrosis factor-alpha (TNF-α) and expression of inducible cyclo-oxygenase (COX-2), nitric oxide synthase (NOS-2), and matrix metalloproteinases (MMP-3 and -9) in canine aqueous humor following repeated anterior chamber paracenteses (ACP). Phase II: to evaluate the effect of carprofen on PGE(2) , NO(x) , and TNF-α in canine aqueous humor following ACP. Four beagles in phase I and 8 beagles in phase II. Phase I: ACP was performed at time (T) 0, 4 and 8 h. Phase II: A randomized, placebo-controlled cross-over design with four dogs per group where carprofen was given 4.4 mg/kg/day on day (D) 1, 2 and 3. ACP was performed at T0 and T1.5 on D3. Statistical analysis was performed with repeated measures anova and post hoc Tukey-Kramer multiple-comparison procedure. In phase II, TNF-α level was analyzed with a Wilcoxon signed-rank test. Phase I: PGE(2) significantly increased (P < 0.0001) to plateau at T4. NO(X) was decreased at T4 (P < 0.06), but increased at T8 (P < 0.0001). COX-2 showed detectable expression only at T8. TNF-α, NOS-2, MMP-3 and -9 were undetectable at all time points. Phase II: At T1.5, PGE(2) was significantly elevated in both groups but was lower in the carprofen group (P = 0.037). NO(x) and TNF-α did not statistically increase in either group. Following ACP, significant increases in PGE(2) levels confirmed inflammation characterized by a rise of COX-2. The NO(x) pathway took longer to induce as compared with PGE(2) . Carprofen decreased PGE(2) levels and could help control intraocular inflammation. © 2011 American College of Veterinary Ophthalmologists.

Synergism between fentanyl and tramadol in tonic inflammatory pain: the orofacial formalin test.

PubMed

Miranda, Hugo F; Noriega, Viviana; Zepeda, Ramiro J; Sierralta, Fernando; Prieto, Juan C

2012-06-01

Opioids have been used for long time to management of pain, the coadministration of two opioids may induce synergism. The present study was conducted to determine the antinociceptive interaction between the dual mechanism of action of tramadol compared to the main of fentanyl antinociception in the orofacial formalin which represents a model of persistent cutaneous nociception in the region innervated by the trigeminal nerve. The i.p. administration of tramadol and fentanyl induced a dose-dependent antinociception with an ED(50) of 2.97 ± 0.32 mg/kg for phase I and 1.79 ± 0.30 mg/kg for phase II and 0.062 ± 0.0040 mg/kg in phase I and 0.041 ± 0.0039 mg/kg in phase II, respectively. The coadministration of fentanyl with tramadol induced synergism in both phases of the test with an interaction index of 0.343 and 0.163 for phase I and phase II, respectively. This finding could be explained by the more complex pharmacology of tramadol compared to fentanyl.

The phase diagram of water at negative pressures: virtual ices.

PubMed

Conde, M M; Vega, C; Tribello, G A; Slater, B

2009-07-21

The phase diagram of water at negative pressures as obtained from computer simulations for two models of water, TIP4P/2005 and TIP5P is presented. Several solid structures with lower densities than ice Ih, so-called virtual ices, were considered as possible candidates to occupy the negative pressure region of the phase diagram of water. In particular the empty hydrate structures sI, sII, and sH and another, recently proposed, low-density ice structure. The relative stabilities of these structures at 0 K was determined using empirical water potentials and density functional theory calculations. By performing free energy calculations and Gibbs-Duhem integration the phase diagram of TIP4P/2005 was determined at negative pressures. The empty hydrates sII and sH appear to be the stable solid phases of water at negative pressures. The phase boundary between ice Ih and sII clathrate occurs at moderate negative pressures, while at large negative pressures sH becomes the most stable phase. This behavior is in reasonable agreement with what is observed in density functional theory calculations.

Dendritic cells and anergic type I NKT cells play a crucial role in sulfatide-mediated immune regulation in experimental autoimmune encephalomyelitis

PubMed Central

Maricic, Igor; Halder, Ramesh; Bischof, Felix; Kumar, Vipin

2014-01-01

CD1d-restricted NKT cells can be divided into two groups: type I NKT cells utilize a semi-invariant TCR whereas type II express a relatively diverse set of TCRs. A major subset of type II NKT cells recognizes myelin-derived sulfatides and is selectively enriched in the central nervous system tissue during experimental autoimmune encephalomyelitis (EAE). We have shown that activation of sulfatide-reactive type II NKT cells by sulfatide prevents induction of EAE. Here we have addressed the mechanism of regulation as well as whether a single immunodominant form of synthetic sulfatide can treat ongoing chronic and relapsing EAE in SJL/J mice. We have shown that the activation of sulfatide-reactive type II NKT cells leads to a significant reduction in the frequency and effector function of PLP139-151/I-As–tetramer+ cells in lymphoid and CNS tissues. In addition, type I NKT cells and dendritic cells in the periphery as well as CNS-resident microglia are inactivated following sulfatide administration, and mice deficient in type I NKT cells are not protected from disease. Moreover tolerized DCs from sulfatide-treated animals can adoptively transfer protection into naive mice. Treatment of SJL/J mice with a synthetic cis-tetracosenoyl sulfatide, but not αGalCer, reverses ongoing chronic and relapsing EAE. Our data highlight a novel immune regulatory pathway involving NKT subset interactions leading to inactivation of type I NKT cells, DCs, and microglial cells in suppression of autoimmunity. Since CD1 molecules are non-polymorphic, the sulfatide-mediated immune regulatory pathway can be targeted for development of non-HLA-dependent therapeutic approaches to T cell-mediated autoimmune diseases. PMID:24973441

Treatment of a Patient with Borderline Personality Disorder Based on Phase-Oriented Model of Eye Movement Desensitization and Reprocessing (EMDR): A Case Report.

PubMed

Momeni Safarabad, Nahid; Asgharnejad Farid, Ali-Asghar; Gharraee, Banafsheh; Habibi, Mojtaba

2018-01-01

Objective: This study aimed at reporting the effect of the 3-phase model of eye movement desensitization and reprocessing in the treatment of a patient with borderline personality disorder. Method : A 33-year-old female, who met the DSM-IV-TR criteria for borderline personality disorder, received a 20-session therapy based on the 3-phase model of eye movement desensitization and reprocessing. Borderline Personality Disorder Checklist (BPD-Checklist), Dissociative Experience Scale (DES-II), Beck Depression Inventory-II-second edition (BDI-II), and Anxiety Inventory (BAI) were filled out by the patient at all treatment phases and at the 3- month follow- up. Results: According to the obtained results, the patient's pretest scores in all research tools were 161, 44, 37, and 38 for BPD-Checklist, DES-II, BDI-II, and BAI, respectively. After treatment, these scores decreased significantly (69, 14, 6 and 10 respectively). So, the patient exhibited improvement in borderline personality disorder, dissociative, depression and anxiety symptoms, which were maintained after the 3-month follow-up. Conclusion: The results supported the positive effect of phasic model of eye movement desensitization and reprocessing on borderline personality disorder.

Structural stability of methane hydrate at high pressures

USGS Publications Warehouse

Shu, J.; Chen, X.; Chou, I-Ming; Yang, W.; Hu, Jiawen; Hemley, R.J.; Mao, Ho-kwang

2011-01-01

The structural stability of methane hydrate under pressure at room temperature was examined by both in-situ single-crystal and powder X-ray diffraction techniques on samples with structure types I, II, and H in diamond-anvil cells. The diffraction data for types II (sII) and H (sH) were refined to the known structures with space groups Fd3m and P63/mmc, respectively. Upon compression, sI methane hydrate transforms to the sII phase at 120 MPa, and then to the sH phase at 600 MPa. The sII methane hydrate was found to coexist locally with sI phase up to 500 MPa and with sH phase up to 600 MPa. The pure sH structure was found to be stable between 600 and 900 MPa. Methane hydrate decomposes at pressures above 3 GPa to form methane with the orientationally disordered Fm3m structure and ice VII (Pn3m). The results highlight the role of guest (CH4)-host (H2O) interactions in the stabilization of the hydrate structures under pressure.

Treatment of a Patient with Borderline Personality Disorder Based on Phase-Oriented Model of Eye Movement Desensitization and Reprocessing (EMDR): A Case Report

PubMed Central

Momeni Safarabad, Nahid; Asgharnejad Farid, Ali-Asghar; Gharraee, Banafsheh; Habibi, Mojtaba

2018-01-01

Objective: This study aimed at reporting the effect of the 3-phase model of eye movement desensitization and reprocessing in the treatment of a patient with borderline personality disorder. Method : A 33-year-old female, who met the DSM-IV-TR criteria for borderline personality disorder, received a 20-session therapy based on the 3-phase model of eye movement desensitization and reprocessing. Borderline Personality Disorder Checklist (BPD-Checklist), Dissociative Experience Scale (DES-II), Beck Depression Inventory-II-second edition (BDI-II), and Anxiety Inventory (BAI) were filled out by the patient at all treatment phases and at the 3- month follow- up. Results: According to the obtained results, the patient’s pretest scores in all research tools were 161, 44, 37, and 38 for BPD-Checklist, DES-II, BDI-II, and BAI, respectively. After treatment, these scores decreased significantly (69, 14, 6 and 10 respectively). So, the patient exhibited improvement in borderline personality disorder, dissociative, depression and anxiety symptoms, which were maintained after the 3-month follow-up. Conclusion: The results supported the positive effect of phasic model of eye movement desensitization and reprocessing on borderline personality disorder. PMID:29892320

New lipid family that forms inverted cubic phases in equilibrium with excess water: molecular structure-aqueous phase structure relationship for lipids with 5,9,13,17-tetramethyloctadecyl and 5,9,13,17-tetramethyloctadecanoyl chains.

PubMed

Yamashita, Jun; Shiono, Manzo; Hato, Masakatsu

2008-10-02

With a view to discovering a new family of lipids that form inverted cubic phases, the aqueous phase behavior of a series of lipids with isoprenoid-type hydrophobic chains has been examined over a temperature range from -40 to 65 degrees C by using optical microscopy, DSC (differential scanning calorimetry), and SAXS (small-angle X-ray scattering) techniques. The lipids examined are those with 5,9,13,17-tetramethyloctadecyl and 5,9,13,17-tetramethyloctadecanoyl chains linked to a series of headgroups, that is, erythritol, pentaerythritol, xylose, and glucose. All of the lipid/water systems displayed a "water + liquid crystalline phase" two-phase coexistence state when sufficiently diluted. The aqueous phase structures of the most diluted liquid crystalline phases in equilibrium with excess water depend both on the lipid molecular structure and on the temperature. Given an isoprenoid chain, the preferred phase consistently follows a phase sequence of an H II (an inverted hexagonal phase) to a Q II (an inverted bicontinuous cubic phase) to an L alpha (a lamellar phase) as A* (cross-section area of the headgroup) increases. For a given lipid/water system, the phase sequence observed as the temperature increases is L alpha to Q II to H II. The present study allowed us to find four cubic phase-forming lipid species, PEOC 18+4 [mono- O-(5,9,13,17-tetramethyloctadecyl)pentaerythritol], beta-XylOC 18+4 [1- O-(5,9,13,17-tetramethyloctadecyl)-beta- d-xylopyranoside], EROCOC 17+4 [1- O-(5,9,13,17-tetramethyloctadecanoyl)erythritol], and PEOCOC 17+4 [mono- O-(5,9,13,17-tetramethyloctadecanoyl)pentaerythritol]. The values of T K (hydrated solid-liquid crystalline phase transition temperature) of the cubic phase-forming lipids are all below 0 degrees C. Quantitative analyses of the lipid molecular structure-aqueous phase structure relationship in terms of the experimentally evaluated "surfactant parameter" allow us to rationally select an optimum combination of hydrophilic/hydrophobic part of a lipid molecule that will form a desired phase in a desired temperature range.

Assessing Hospital Disaster Readiness Over Time at the US Department of Veterans Affairs.

PubMed

Der-Martirosian, Claudia; Radcliff, Tiffany A; Gable, Alicia R; Riopelle, Deborah; Hagigi, Farhad A; Brewster, Pete; Dobalian, Aram

2017-02-01

Introduction There have been numerous initiatives by government and private organizations to help hospitals become better prepared for major disasters and public health emergencies. This study reports on efforts by the US Department of Veterans Affairs (VA), Veterans Health Administration, Office of Emergency Management's (OEM) Comprehensive Emergency Management Program (CEMP) to assess the readiness of VA Medical Centers (VAMCs) across the nation. Hypothesis/Problem This study conducts descriptive analyses of preparedness assessments of VAMCs and examines change in hospital readiness over time. To assess change, quantitative analyses of data from two phases of preparedness assessments (Phase I: 2008-2010; Phase II: 2011-2013) at 137 VAMCs were conducted using 61 unique capabilities assessed during the two phases. The initial five-point Likert-like scale used to rate each capability was collapsed into a dichotomous variable: "not-developed=0" versus "developed=1." To describe changes in preparedness over time, four new categories were created from the Phase I and Phase II dichotomous variables: (1) rated developed in both phases; (2) rated not-developed in Phase I but rated developed in Phase II; (3) rated not-developed in both phases; and (4) rated developed in Phase I but rated not- developed in Phase II. From a total of 61 unique emergency preparedness capabilities, 33 items achieved the desired outcome - they were rated either "developed in both phases" or "became developed" in Phase II for at least 80% of VAMCs. For 14 items, 70%-80% of VAMCs achieved the desired outcome. The remaining 14 items were identified as "low-performing" capabilities, defined as less than 70% of VAMCs achieved the desired outcome. Measuring emergency management capabilities is a necessary first step to improving those capabilities. Furthermore, assessing hospital readiness over time and creating robust hospital readiness assessment tools can help hospitals make informed decisions regarding allocation of resources to ensure patient safety, provide timely access to high-quality patient care, and identify best practices in emergency management during and after disasters. Moreover, with some minor modifications, this comprehensive, all-hazards-based, hospital preparedness assessment tool could be adapted for use beyond the VA. Der-Martirosian C , Radcliff TA , Gable AR , Riopelle D , Hagigi FA , Brewster P , Dobalian A . Assessing hospital disaster readiness over time at the US Department of Veterans Affairs. Prehsop Disaster Med. 2017;32(1):46-57.

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.

LED street lighting evaluation -- phase II : LED specification and life-cycle cost analysis.

DOT National Transportation Integrated Search

2015-01-01

Phase II of this study focused on developing a draft specification for LED luminaires to be used by IDOT : and a life-cycle cost analysis (LCCA) tool for solid state lighting technologies. The team also researched the : latest developments related to...

Medulloblastoma in children and adolescents: a systematic review of contemporary phase I and II clinical trials and biology update.

PubMed

Bautista, Francisco; Fioravantti, Victoria; de Rojas, Teresa; Carceller, Fernando; Madero, Luis; Lassaletta, Alvaro; Moreno, Lucas

2017-11-01

Survival rates for patients with medulloblastoma have improved in the last decades but for those who relapse outcome is dismal and new approaches are needed. Emerging drugs have been tested in the last two decades within the context of phase I/II trials. In parallel, advances in genetic profiling have permitted to identify key molecular alterations for which new strategies are being developed. We performed a systematic review focused on the design and outcome of early-phase trials evaluating new agents in patients with relapsed medulloblastoma. PubMed, clinicaltrials.gov, and references from selected studies were screened to identify phase I/II studies with reported results between 2000 and 2015 including patients with medulloblastoma aged <18 years. A total of 718 studies were reviewed and 78 satisfied eligibility criteria. Of those, 69% were phase I; 31% phase II. Half evaluated conventional chemotherapeutics and 35% targeted agents. Overall, 662 patients with medulloblastoma/primitive neuroectodermal tumors were included. The study designs and the response assessments were heterogeneous, limiting the comparisons among trials and the correct identification of active drugs. Median (range) objective response rate (ORR) for patients with medulloblastoma in phase I/II studies was 0% (0-100) and 6.5% (0-50), respectively. Temozolomide containing regimens had a median ORR of 16.5% (0-100). Smoothened inhibitors trials had a median ORR of 8% (3-8). Novel drugs have shown limited activity against relapsed medulloblastoma. Temozolomide might serve as backbone for new combinations. Novel and more homogenous trial designs might facilitate the development of new drugs. © 2017 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

Phase I/II Study of Weekly Oraxol for the Second-Line Treatment of Patients With Metastatic or Recurrent Gastric Cancer

PubMed Central

Lee, Keun-Wook; Lee, Kyung Hee; Zang, Dae Young; Park, Young Iee; Shin, Dong Bok; Kim, Jin Won; Im, Seock-Ah; Koh, Sung Ae; Cho, Joo-Youn; Jung, Jin-A

2015-01-01

Lessons Learned Oraxol, a novel oral formulation of paclitaxel, displayed modest efficacy as second-line chemotherapy for gastric cancer. Considering its favorable toxicity profiles, further studies are warranted in various solid tumors including gastric cancer. Background. Oraxol consists of paclitaxel and HM30181A, a P-glycoprotein inhibitor, to increase the oral bioavailability of paclitaxel. This phase I/II study (HM-OXL-201) was conducted to determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of Oraxol. In addition, we investigated the efficacy and safety of Oraxol as second-line chemotherapy for metastatic or recurrent gastric cancer (GC). Methods. In the phase I component, paclitaxel was orally administered at escalating doses (90, 120, or 150 mg/m2 per day) with a fixed dose (15 mg/day) of HM30181A. Oraxol was administrated 6 times per cycle (days 1, 2, 8, 9, 15, and 16) every 4 weeks. In the phase II component, the efficacy and safety of Oraxol were evaluated. Results. In the phase I component, the MTD could not be determined. Based on toxicity and pharmacokinetic data, the RP2D of oral paclitaxel was determined to be 150 mg/m2. In the phase II component, 4 of 43 patients (9.3%) achieved partial responses. Median progression-free survival and overall survival were 2.6 and 10.7 months, respectively. Toxicity profiles were favorable, and the most common drug-related adverse events (grade ≥3) were neutropenia and diarrhea. Conclusion. Oraxol exhibited modest efficacy and favorable toxicity profiles as second-line chemotherapy for GC. PMID:26112004

New stable ternary alkaline-earth metal Pb(II) oxides: Ca / Sr / BaPb 2 O 3 and BaPbO 2

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

Li, Yuwei; Zhang, Lijun; Singh, David J.

The different but related chemical behaviors of Pb(II) oxides compared to Sn(II) oxides, and the existence of known alkali/alkali-earth metal Sn(II) ternary phases, suggest that there should be additional ternary Pb(II) oxide phases. Here, we report structure searches on the ternary alkaline-earth metal Pb(II) oxides leading to four new phases. These are two ternary Pb(II) oxides, SrPb 2O 3 and BaPb 2O 3, which have larger chemical potential stability ranges compared with the corresponding Sn(II) oxides, and additionally two other ternary Pb(II) oxides, CaPb 2O 3 and BaPbO 2, for which there are no corresponding Sn(II) oxides. Those Pb(II) oxidesmore » are stabilized by Pb-rich conditions. These structures follow the Zintl behavior and consist of basic structural motifs of (PbO 3) 4- anionic units separated and stabilized by the alkaline-earth metal ions. They show wide band gaps ranging from 2.86 to 3.12 eV, and two compounds (CaPb 2O 3 and SrPb 2O 3) show rather light hole effective masses (around 2m 0). The valence band maxima of these compounds have a Pb-6s/O-2p antibonding character, which may lead to p-type defect (or doping) tolerant behavior. This then suggests alkaline-earth metal Pb(II) oxides may be potential p-type transparent conducting oxides.« less