1. Historic American Buildings Survey Eli Lilly Company Photographic Department ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

1. Historic American Buildings Survey Eli Lilly Company Photographic Department - About 1937-1938 Gift courtesy of Edward D. James, FAIA, Preservation Officer GENERAL VIEW OF TRADING POST (LEFT) AND CABIN OF WILLIAM CONNER (RIGHT) AFTER RESTORATION - William Conner Trading Post, State Highway 234, Noblesville, Hamilton County, IN

L.U.St: a tool for approximated maximum likelihood supertree reconstruction.

PubMed

Akanni, Wasiu A; Creevey, Christopher J; Wilkinson, Mark; Pisani, Davide

2014-06-12

Supertrees combine disparate, partially overlapping trees to generate a synthesis that provides a high level perspective that cannot be attained from the inspection of individual phylogenies. Supertrees can be seen as meta-analytical tools that can be used to make inferences based on results of previous scientific studies. Their meta-analytical application has increased in popularity since it was realised that the power of statistical tests for the study of evolutionary trends critically depends on the use of taxon-dense phylogenies. Further to that, supertrees have found applications in phylogenomics where they are used to combine gene trees and recover species phylogenies based on genome-scale data sets. Here, we present the L.U.St package, a python tool for approximate maximum likelihood supertree inference and illustrate its application using a genomic data set for the placental mammals. L.U.St allows the calculation of the approximate likelihood of a supertree, given a set of input trees, performs heuristic searches to look for the supertree of highest likelihood, and performs statistical tests of two or more supertrees. To this end, L.U.St implements a winning sites test allowing ranking of a collection of a-priori selected hypotheses, given as a collection of input supertree topologies. It also outputs a file of input-tree-wise likelihood scores that can be used as input to CONSEL for calculation of standard tests of two trees (e.g. Kishino-Hasegawa, Shimidoara-Hasegawa and Approximately Unbiased tests). This is the first fully parametric implementation of a supertree method, it has clearly understood properties, and provides several advantages over currently available supertree approaches. It is easy to implement and works on any platform that has python installed. bitBucket page - https://afro-juju@bitbucket.org/afro-juju/l.u.st.git. Davide.Pisani@bristol.ac.uk.

Lillie Burney Elementary School

NASA Technical Reports Server (NTRS)

2006-01-01

Mississippi Rep. Percy Watson (left) talks with first-graders Savannah Jones and Levi Meyers, and Astronaut Lee Morin on Sept. 8 during the NASA Explorer School kickoff event at the Lillie Burney Elementary School in Hattiesburg, Miss. NASA Explorer Schools help promote student achievement in mathematics and science through activities using the excitement of NASA research, discoveries and missions.

Lillie Burney Elementary School

NASA Image and Video Library

2006-09-08

Mississippi Rep. Percy Watson (left) talks with first-graders Savannah Jones and Levi Meyers, and Astronaut Lee Morin on Sept. 8 during the NASA Explorer School kickoff event at the Lillie Burney Elementary School in Hattiesburg, Miss. NASA Explorer Schools help promote student achievement in mathematics and science through activities using the excitement of NASA research, discoveries and missions.

Risk analysis for worker exposure to benzene

NASA Astrophysics Data System (ADS)

Hallenbeck, William H.; Flowers, Roxanne E.

1992-05-01

Cancer risk factors (characterized by route, dose, dose rate per kilogram, fraction of lifetime exposed, species, and sex) were derived for workers exposed to benzene via inhalation or ingestion. Exposure at the current Occupational Safety and Health Administration (OSHA) permissible exposure limit (PEL) and at leaking underground storage tank (LUST) sites were evaluated. At the current PEL of 1 ppm, the theoretical lifetime excess risk of cancer from benzene inhalation is ten per 1000. The theoretical lifetime excess risk for worker inhalation exposure at LUST sites ranged from 10 to 40 per 1000. These results indicate that personal protection should be required. The theoretical lifetime excess risk due to soil ingestion is five to seven orders of magnitude less than the inhalation risks.

77 FR 60622 - New Animal Drugs; Change of Sponsor's Address; Monensin; Spinosad; Tilmicosin

Federal Register 2010, 2011, 2012, 2013, 2014

2012-10-04

...; Tilmicosin AGENCY: Food and Drug Administration, HHS. ACTION: Final rule. SUMMARY: The Food and Drug... \\1\\ A Division of Eli (tilmicosin use in two-way, 558.618 Lilly & Co., Lilly phosphate) plus...) * * * (iv) Tilmicosin alone or in combination as in Sec. 558.618. * * * * * 0 7. In Sec. 558.618, remove and...

Teaching Undergraduates. Essays from the Lilly Endowment Workshop on Liberal Arts.

ERIC Educational Resources Information Center

Kimball, Bruce A., Ed.

The Lilly Endowment has a long-standing commitment to supporting liberal arts programs and teaching at the undergraduate level. The Endowment-sponsored summer workshop on the liberal arts, held annually at Colorado College, has a 28-year history. It offers professors and deans from a variety of colleges and universities the opportunity to study a…

Spatio-temporal dynamics of the mirror neuron system during social intentions.

PubMed

Cacioppo, Stephanie; Bolmont, Mylene; Monteleone, George

2017-10-27

Previous research has shown that specific goals and intentions influence a person's allocation of social attention. From a neural viewpoint, a growing body of evidence suggests that the inferior fronto-parietal network, including the mirror neuron system, plays a role in the planning and the understanding of motor intentions. However, it is unclear whether and when the mirror neuron system plays a role in social intentions. Combining a behavioral task with electrical neuroimaging in 22 healthy male participants, the current study investigates whether the temporal brain dynamic of the mirror neuron system differs during two types of social intentions i.e., lust vs. romantic intentions. Our results showed that 62% of the stimuli evoking lustful intentions also evoked romantic intentions, and both intentions were sustained by similar activations of the inferior frontal gyrus and the inferior parietal lobule/angular gyrus for the first 432 ms after stimulus onset. Intentions to not love or not lust, on the other hand, were characterized by earlier differential activations of the inferior fronto-parietal network i.e., as early as 244 ms after stimulus onset. These results suggest that the mirror neuron system may not only code for the motor correlates of intentions, but also for the social meaning of intentions and its valence at both early/automatic and later/more elaborative stages of information processing.

Integrating biofiltration with SVE: A case study

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

Lesley, M.P.; Rangan, C.R.

1996-12-01

A prototype integrated soil vacuum extraction/biofiltration system has been designed and installed at a gasoline contaminated LUST site in southern Delaware. The prototype system remediates contaminated moisture entrained in the air stream, employs automatic water level controls in the filters, and achieves maximum vapor extraction and VOC destruction efficiency with an optimum power input. In addition, the valving and piping layout allows the direction of air flow through the filters to be reversed at a given time interval, which minimizes biofouling, thereby increasing efficiency by minimizing the need for frequent cleaning. This integrated system achieves constant VOC destruction rates ofmore » 40 to 70% while maintaining optimal VOC removal rates from the subsurface. The modular design allows for easy mobilization, setup and demobilization at state-lead LUST sites throughout Delaware.« less

Pim-1: A Molecular Target to Modulate Cellular Resistance to Therapy in Prostate Cancer

DTIC Science & Technology

2005-10-01

Reiter RE, Lilly MB: Gene expression profiling in R- flurbiprofen -treated prostate cancer: Identification of prostate stem cell antigen as a... flurbiprofen -regulated gene. (submitted, 2006). 51. Holder SL, Zemskova M, Bremner R, Neidigh J, Lilly MB: Identification of specific, cell-permeable...profiling in R- flurbiprofen - treated prostate cancer: Identification of prostate stem cell antigen as a flurbiprofen - regulated gene. (poster

Identifying Emotions on the Basis of Neural Activation

PubMed Central

Kassam, Karim S.; Markey, Amanda R.; Cherkassky, Vladimir L.; Loewenstein, George; Just, Marcel Adam

2013-01-01

We attempt to determine the discriminability and organization of neural activation corresponding to the experience of specific emotions. Method actors were asked to self-induce nine emotional states (anger, disgust, envy, fear, happiness, lust, pride, sadness, and shame) while in an fMRI scanner. Using a Gaussian Naïve Bayes pooled variance classifier, we demonstrate the ability to identify specific emotions experienced by an individual at well over chance accuracy on the basis of: 1) neural activation of the same individual in other trials, 2) neural activation of other individuals who experienced similar trials, and 3) neural activation of the same individual to a qualitatively different type of emotion induction. Factor analysis identified valence, arousal, sociality, and lust as dimensions underlying the activation patterns. These results suggest a structure for neural representations of emotion and inform theories of emotional processing. PMID:23840392

Identifying Emotions on the Basis of Neural Activation.

PubMed

Kassam, Karim S; Markey, Amanda R; Cherkassky, Vladimir L; Loewenstein, George; Just, Marcel Adam

2013-01-01

We attempt to determine the discriminability and organization of neural activation corresponding to the experience of specific emotions. Method actors were asked to self-induce nine emotional states (anger, disgust, envy, fear, happiness, lust, pride, sadness, and shame) while in an fMRI scanner. Using a Gaussian Naïve Bayes pooled variance classifier, we demonstrate the ability to identify specific emotions experienced by an individual at well over chance accuracy on the basis of: 1) neural activation of the same individual in other trials, 2) neural activation of other individuals who experienced similar trials, and 3) neural activation of the same individual to a qualitatively different type of emotion induction. Factor analysis identified valence, arousal, sociality, and lust as dimensions underlying the activation patterns. These results suggest a structure for neural representations of emotion and inform theories of emotional processing.

When first comes love (or lust): how romantic and sexual cues bias first impressions in online social networking.

PubMed

Dillman Carpentier, Francesca R; Parrott, M Scott; Northup, C Temple

2014-01-01

Three experimental studies (N = 286) tested how priming the concepts of sex or romance influence the way people perceive other social media users. Participants first completed a word-search task containing sexual (intercourse, lust), romantic (love, heart), or control words. Participants then evaluated a target's sexual qualities and romantic qualities based on social media profiles, as well as rated their acceptance of the priming stimuli. Results suggested that sex primes led participants to judge targets as being more alluring, racy, and provocative, whereas romance primes led participants to judge targets as being more tender, sentimental, and kind. Both men and women found all primes to be equally acceptable content; women were not averse to these mainstream, non-explicit sexual stimuli. Findings are discussed in terms of viewing sex and romance as distinct, yet related networks of concepts and the need to disentangle sex, romance, and sexualized views of romance.

Different insulin concentrations in resuspended vs. unsuspended NPH insulin: Practical aspects of subcutaneous injection in patients with diabetes.

PubMed

Lucidi, P; Porcellati, F; Marinelli Andreoli, A; Candeloro, P; Cioli, P; Bolli, G B; Fanelli, C G

2017-06-06

This study measured the insulin concentration (Ins [C] ) of NPH insulin in vials and cartridges from different companies after either resuspension (R+) or not (R-; in the clear/cloudy phases of unsuspended NPH). Measurements included Ins [C] in NPH(R+) and in the clear/cloudy phases of NPH(R-), and the time needed to resuspend NPH and time for NPH(R+) to separate again into clear/cloudy parts. In vials of NPH(R+) (assumed to be 100%), Ins [C] in the clear phase of NPH(R-) was<1%, but 230±41% and 234±54% in the cloudy phases of Novo Nordisk and Eli Lilly NPH, respectively. Likewise, in pen cartridges, Ins [C] in the clear phase of NPH(R-) was<1%, but 182±33%, 204±22% and 229±62% in the cloudy phases of Novo, Lilly and Sanofi NPH. Time needed to resuspend NPH (spent in tipping) in vials was brief with both Novo (5±1s) and Lilly NPH (6±1s), but longer with all pen cartridges (50±8s, 40±6s and 30±4s from Novo, Lilly and Sanofi, respectively; P=0.022). Time required for 50% separation into cloudy and clear parts of NPH was longer with Novo (60±7min) vs. Lilly (18±3min) in vials (P=0.021), and affected by temperature, but not by the different diameter sizes of the vials. With pen cartridges, separation into clear and cloudy parts was significantly faster than in vials (P<0.01). Ins [C] in NPH preparations varies depending on their resuspension or not. Thus, subcutaneous injection of the same number of units of NPH in patients with diabetes may deliver different amounts of insulin depending on its prior NPH resuspension. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

The National LUST Cleanup Backlog: A Study of Opportunities

EPA Pesticide Factsheets

To understand the makeup of UST releases remaining and why the pace of cleanups is slowing, EPA undertook a two-phase, data-driven analysis of the cleanups remaining as of 2006 (Phase 1) and 2009 (Phase 2).

Gasoline Composition Regulations Affecting LUST Sites

EPA Science Inventory

Passage of the Clean Air Act Amendments in 1990 imposed requirements on gasoline composition in the United States. Impacts to ground water are affected by the provisions that required oxygenated additives and limited benzene concentration. Reformulated and oxygenated gasoline w...

LUST ON-LINE CALCULATOR INTRODUCTION

EPA Science Inventory

EPA has developed a suite of on-line calculators to assist in performing site assessment and modeling calculations for leaking underground storage tank sites (http://www.epa.gov/athens/onsite). The calculators are divided into four types: parameter estimation, models, scientific...

Hawaiian Winter Workshop Proceedings of Parameterization of Small-Scale Processes Held in Manoa, Hawaii on 17-20 January 1989

DTIC Science & Technology

1989-01-01

England while waiting for an outbreak of cold air (Larson, 1988). Even before the arrival of the storm trailing the cold air behind it, both shear and...and simulation of storm -induced mixed-layer deepening. J. Phys. Oceanogr., 8. 582-599. 217 Riley, J.J., and R.W. Metcalf: 1987. Direct numerical...the severe downslope wind storm which occurs in the lee of major mountain barriers (Lilly and Kennedy, 1973: Lilly. 1978) under suitable atmospheric

An Approach for Monitored Natural Attenuation (MNA) at a LUST Site

EPA Science Inventory

The primary mechanism for natural attenuation of fuel components in ground water is aerobic and anaerobic biodegradation of the components. Biodegradation reduces the concentration of oxygen, nitrate and sulfate, and increases the concentrations of iron(II) and methane. Changes...

1. Historic American Buildings Survey Eli Lilly Company Photographic Department ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

1. Historic American Buildings Survey Eli Lilly Company Photographic Department - About 1937-1938 Gift courtesy of Edward D. James, FAIA, Preservation Officer SKETCH PLAN OF FARM Legend: (1) William Conner House; (2) Still house; (3) Milk house; (4) Museum; (5) Loom house; (6) Modern barns, grain and implement storage; (7) Three-eighths of a mile north or here on the river bank, William Conner lived in a double cabin trading post; (8) Trading post; (9) Conner cabin; (10) Pioneer barn - William Conner Prairie Farm, State Highway 234, Noblesville, Hamilton County, IN

USING DIRECT-PUSH TOOLS TO MAP HYDROSTRATIGRAPHY AND PREDICT MTBE PLUME DIVING

EPA Science Inventory

MTBE plumes have been documented to dive beneath screened intervals of conventional monitoring well networks at a number of LUST sites. This behavior makes these plumes difficult both to detect and remediate. Electrical conductivity logging and pneumatic slug testing performed in...

Children's Comprehension of Plural Predicate Conjunction

ERIC Educational Resources Information Center

Tieu, Lyn; Romoli, Jacopo; Poortman, Eva; Winter, Yoad; Crain, Stephen

2018-01-01

Previous developmental studies of conjunction have focused on the syntax of phrasal and sentential coordination (Lust, 1977; de Villiers, Tager-Flusberg & Hakuta, 1977; Bloom, Lahey, Hood, Lifter & Fiess, 1980, among others). The present study examined the flexibility of children's interpretation of conjunction. Specifically, when two…

Exenatide: AC 2993, AC002993, AC2993A, exendin 4, LY2148568.

PubMed

2004-01-01

Exenatide [AC002993, AC2993A, AC 2993, LY2148568, exendin 4], a glucagon-like peptide-1 (GLP-1) agonist, is a synthetic exendin 4 compound under development with Amylin Pharmaceuticals for the treatment of type 2 diabetes. Both exendin 4 and its analogue, exendin 3, are 39-amino acid peptides isolated from Heloderma horridum lizard venom that have different amino acids at positions 2 and 3, respectively. Exendins are able to stimulate insulin secretion in response to rising blood glucose levels, and modulate gastric emptying to slow the entry of ingested sugars into the bloodstream. Amylin Pharmaceuticals acquired exclusive patent rights for the two exendin compounds (exendin 3 and exendin 4) from the originator, Dr John Eng (Bronx, NY, US). On 20 September 2002, Amylin and Eli Lilly signed a collaborative agreement for the development and commercialisation of exenatide for type 2 diabetes. Under the terms of the agreement, Eli Lilly has paid Amylin a licensing fee of 80 million US dollars and bought Amylin's stock worth 30 million US dollars at 18.69 US dollars a share. After the initial payment, Eli Lilly will pay Amylin up to 85 US dollars million upon reaching certain milestones and also make an additional payment of up to 130 million US dollars upon global commercialisation of exenatide. Both companies will share the US development and commercialisation costs, while Eli Lilly will pick up up to 80% of development costs and all commercialisation costs outside the US. Amylin and Eli Lilly will equally share profit from sales in the US, while Eli Lilly will get 80% of the profit outside the US and Amylin will get the rest. This agreement has also enabled Amylin to train its sales force to co-promote Lilly's human growth hormone Humatrope. Alkermes will receive research and development funding and milestone payments, and also a combination of royalty payments and manufacturing fees based on product sales. Alkermes undertakes the responsibility for the development of several initial formulations of the long-acting drug and manufacturing of the final product, while Amylin will be responsible for clinical trials, regulatory filings and worldwide marketing. The goal of the exenatide LAR programme is to develop a once-a-month injectable formulation of exenatide. In November 2003, Amylin announced positive results from the second of three pivotal, phase III studies that evaluated the effects of exenatide in combination with sulfonylureas in 377 randomised patients with type 2 diabetes. The design of the study was similar to that from the first study. The final third phase III study of exenatide was completed in November 2003. This study investigated the effects of exenatide in combination with metformin and sulfonylureas. Amylin and Eli Lilly announced that all of the pivotal phase III trials met the primary glucose control endpoint as measured by glycosylated haemoglobin. An NDA submission for exenatide is projected for mid-2004. A phase II, dose-ascending study in patients with type 2 diabetes was initiated in June 2002. This multicentre (US), double-blind, placebo-controlled study evaluated the safety, tolerability and the pharmacokinetic profile of exenatide LAR in up to 100 patients with type 2 diabetes. A phase I study of exenatide LAR began in Europe in March 2001 and was completed in Q3 2001. A long-acting, sustained-release formulation of exenatide lowered both pre- and post-meal glucose concentration during a 24h period in patients with type 2 diabetes. In November 2002, analysts at Prudential Financial estimated that exenatide, pending approval, has the potential to reach sales of 477 million US dollars in 2006.

Personality and the Planning Process

DTIC Science & Technology

2001-01-01

personality types, it is fair to note that in 1912 Sigmund Freud (a colleague of Jung’s) found unacceptable Jung’s differing concept of the libido and...environmental stimulation (it worked for dogs). Sigmund Freud claimed that man is driven by instinctual lust, and any higher motives were just

Inactivation of Bacillus Anthracis Spores Using Carbon Nanotubes

DTIC Science & Technology

2014-10-30

S1793984412300129 Marquita Lilly, Liju Yang, Kamal Aferchich. Effect of Single-walled Carbon Nanotubes on Bacillus Anthracis Cell Growth, Sporulation ...addition,  SWNTs  treatment  did  not  induce  sporulation  of B. anthracis.  [Aferichich, et al. 2012]. 2)  SWNTs  in  combination with oxidizing agents...8. Kamal Aferchich, Marquita Lilly, Liju Yang*. 2012. Effect of Single‐walled Carbon Nanotubes on  Bacillus Anthracis Cell Growth,  Sporulation , and

What's the Deal with Methane at LUST Spill Sites? Part 2: Vapor Intrusion

EPA Science Inventory

This article is specifically intended to discuss methane produced from releases of ethanol and gasoline-ethanol mixtures. There may be other sources of methane at a site, including leaks of natural gas or methane produced from the natural decay of buried plant tissues or from the...

What's the Deal with Methane at LUST Spill Sites? Part 1

EPA Science Inventory

This article is specifically intended to discuss methane produced from releases of ethanol and gasoline-ethanol mixtures. There may be other sources of methane at a site, including leaks of natural gas or methane produced from the natural decay of buried plant tissues or from th...

USING SIMPLE MATHEMATICAL MODELS FOR ESTIMATING IMPACTS TO GROUND WATER AT PETROLEUM RELEASE SITES - WORKSHOP

EPA Science Inventory

Regulators and consultants alike are routinely tasked with predicting potential future impacts to ground water resources from leaking underground storage tank (LUST) sites. Site data is usually sparse, variable, and uncertain at best. However, this type of data can be evaluated ...

Augustine the African: Critic of Roman Colonialist Discourse.

ERIC Educational Resources Information Center

Troup, Calvin L.

1995-01-01

Offers a reading of St. Augustine that suggests his work as prescient of, and harmonious with, contemporary criticism of colonialist discourse rather than as an authorizing voice for European imperialism. Looks also at a Stephen Greenblatt essay that comments on the relationship between Christianity and national lust for empire. (TB)

Lusting after Children: The Tobacco Industry's Investment in a Profitable Future.

ERIC Educational Resources Information Center

Tye, Joe B.

1988-01-01

Argues that the tobacco industry deliberately uses advertising to influence young people to experiment with tobacco. Advertisements in sports, entertainment and sex-oriented magazines, outdoor advertising, and promotions in youth-oriented movies are all intended to influence young people. Lists actions individuals can take to reduce the influence…

Folk Literature of South Asia.

ERIC Educational Resources Information Center

Wadley, Susan S., Ed.

1975-01-01

The collection of articles in this volume focuses on different kinds of folk literature from Bengal, Tamilnad, Bihar, Hindi-speaking North India, and Nepal. An introductory article by S.S. Wadley discusses types of folk literature in Karimpur. The remaining articles are organized according to cultural themes: "The Lustful Stepmother in the…

NACA Pilots at the Aircraft Engine Research Laboratory

NASA Image and Video Library

1945-07-21

The Aircraft Engine Research Laboratory’s pilot corps during the final days of World War II: from left to right, Joseph Vensel, Howard Lilly, William Swann, and Joseph Walker. William “Eb” Gough joined the group months after this photograph. These men were responsible for flying the various National Advisory Committee for Aeronautics (NACA) aircraft to test new engine modifications, study ice buildup, and determine fuel performance. Vensel, a veteran pilot from Langley, was the Chief of Flight Operations and a voice of reason at the laboratory. In April 1947 Vensel was transferred to lead the new Muroc Flight Tests Unit in California until 1966. Lilly was a young pilot with recent Navy experience. Lilly also flew in the 1946 National Air Races. He followed Vensel to Muroc in July 1947 where he became the first NACA pilot to penetrate the sound barrier. On May 3, 1948, Lilly became the first NACA pilot to die in the line of duty. Swann was a young civilian pilot when he joined the NACA. He spent his entire career at the Cleveland laboratory, and led the flight operations group from the early 1960s until 1979. Two World War II veterans joined the crew after the war. Walker was a 24-year-old P–38 reconnaissance pilot. He joined the NACA as a physicist in early 1945 but soon worked his way into the cadre of pilots. Walker later gained fame as an X-plane pilot at Muroc and was killed in a June 1966 fatal crash. Gough survived being shot down twice during the war and was decorated for flying rescue missions in occupied areas.

Red-Hot Library Lust

ERIC Educational Resources Information Center

Benton, Thomas H.

2007-01-01

Thomas Benton (a pseudonym of an associate professor of English at a Midwestern liberal-arts college) describes most college libraries of today as being clean and well-lighted, with metal shelving, veneered tabletops, and banks of computers. He fears that in 20 years, college students will regard books as a "quaint technology"--the way they now…

Installation Restoration Program. Phase I: Records Search Willow Grove Air Reserve Facility, Willow Grove, Pennsylvania.

DTIC Science & Technology

1984-11-01

FLOW CHART Complet List of Location/Shtes Evaluation of Past Operations at LUste SNMe * ~Potential Hazard to Healh WelareS Reglaor Agencon consolidat...siting studies were also a part of this tions, soil, groundwater sampling and large complex project. analysis, and remedial concept engi- neering. Project

Going Big or Going Home!

NASA Astrophysics Data System (ADS)

Riendeau, Diane

2013-04-01

It seems to me that people are going to greater extremes to get thrills these days. Amusement park rides are getting tall and faster. Sky diving is becoming a ``normal'' thing to do to celebrate your birthday. To acknowledge this lust for bigger and better, I put together a few videos that I thought might fit the bill.

Stereotypes of Latin Americans Perpetuated in Secondary School History Textbooks.

ERIC Educational Resources Information Center

Cruz, Barbara C.

1994-01-01

This study reviewed six history textbooks widely used in grades 7-12 across the U.S. Using a story-line analysis, the findings of this study suggest: (1) textbooks reinforce negative stereotypes of Latin Americans as lazy, passive, irresponsible, and, somewhat paradoxically, lustful, animalistic and violent; (2) the method of description employed…

Teaching Critical Literacy across the Curriculum in Multimedia America.

ERIC Educational Resources Information Center

Semali, Ladislaus M.

The teaching of media texts as a form of textual construction is embedded in the assumption that audiences bring individual preexisting dispositions even though the media may contribute to their shaping of basic attitudes, beliefs, values, and behavior. As summed up by D. Lusted, at the core of such textual construction are basic assumptions that…

Zombie Politics and Other Late Modern Monstrosities in the Age of Disposability

ERIC Educational Resources Information Center

Giroux, Henry A.

2010-01-01

At present Americans are fascinated by a particular kind of monstrosity, by vampires and zombies condemned to live an eternity by feeding off the souls of the living. The preoccupation with such parasitic relations speaks uncannily to the threat most Americans perceive from the shameless blood lust of contemporary captains of industry, which Matt…

Ketamine: stimulating antidepressant treatment?

PubMed

Malhi, Gin S; Byrow, Yulisha; Cassidy, Frederick; Cipriani, Andrea; Demyttenaere, Koen; Frye, Mark A; Gitlin, Michael; Kennedy, Sidney H; Ketter, Terence A; Lam, Raymond W; McShane, Rupert; Mitchell, Alex J; Ostacher, Michael J; Rizvi, Sakina J; Thase, Michael E; Tohen, Mauricio

2016-05-01

The appeal of ketamine - in promptly ameliorating depressive symptoms even in those with non-response - has led to a dramatic increase in its off-label use. Initial promising results await robust corroboration and key questions remain, particularly concerning its long-term administration. It is, therefore, timely to review the opinions of mood disorder experts worldwide pertaining to ketamine's potential as an option for treating depression and provide a synthesis of perspectives - derived from evidence and clinical experience - and to consider strategies for future investigations. G.S.M. Grant/research support: National Health Medical Research Council, NSW Health, Ramsay Health, American Foundation for Suicide Prevention, AstraZeneca, Eli Lilly & Co, Organon, Pfizer, Servier, and Wyeth; has been a speaker for Abbott, AstraZeneca, Eli Lilly & Co, Janssen Cilag, Lundbeck, Pfizer, Ranbaxy, Servier, and Wyeth; consultant: AstraZeneca, Eli Lilly & Co, Janssen Cilag, Lundbeck, and Servier. M.A.F. Grant support: AssureRx, Janssen Research & Development, Mayo Foundation, Myriad, National Institute of Alcohol Abuse and Alcoholism (NIAAA), National Institute of Mental Health (NIMH), Pfizer. Consultant (Mayo): Janssen Research & Development, LLC, Mitsubishi Tanabe Pharma Corporation, Myriad Genetics, Neuralstem Inc., Sunovion, Supernus Pharmaceuticals, Teva Pharmaceuticals. CME/travel support: American Physician Institute, CME Outfitters. Financial interest/Mayo Clinic 2016: AssureRx. S.H.K. Grant/research support: Brain Canada, Bristol Meyer Squibb, CIHR, Janssen, Johnson & Johnson, Lundbeck, Ontario Brain Institute, Pfizer, Servier, St. Jude Medical, Sunovion. T.A.K. Grant/research support (through Stanford University): Sunovion Pharmaceuticals and Merck & Co., Inc.; consultant/advisory board bember: Allergan, Inc., Janssen Pharmaceuticals, Myriad Genetic Laboratories, Inc., and Sunovion Pharmaceuticals; lecture honoraria (not Speaker's Bureau payments): GlaxoSmithKline, and Sunovion Pharmaceuticals; royalties from American Psychiatric Publishing, Inc. Also, AstraZeneca Pharmaceuticals LP provided publication support to Parexel for preparation of a manuscript. Spouse employee and stockholder of Janssen Pharmaceuticals. R.W.L. Honoraria for speaking/advising/consulting, and/or received research funds: AstraZeneca, Brain Canada, Bristol Myers Squibb, Canadian Institutes of Health Research, Canadian Depression Research and Intervention Network, Canadian Network for Mood and Anxiety Treatments, Canadian Psychiatric Association, Coast Capital Savings, Johnson and Johnson, Lundbeck, Lundbeck Institute, Pfizer, Servier, St. Jude Medical, Takeda University, Health Network Foundation, and Vancouver Coastal Health Research Institute. R.M. Investigator Janssen trials of esketamine; 'paid-for' ketamine clinic operated by Oxford Health NHS Foundation Trust - fees used to support the Trust. M.J.O. Consultant: Sunovion and Acadia Pharmaceuticals. Full-time employee of U.S. Department of Veterans Affairs. M.E.T. Advisory/Consultant: Alkermes, Allergan, AstraZeneca, Bristol-Myers Squibb Company, Cerecor inc., Eli Lilly & Co., Forest Laboratories, Gerson Lehrman Group, Fabre-Kramer Pharmaceuticals, Inc., GlaxoSmithKline, Guidepoint Global, H. Lundbeck A/S, MedAvante Inc., Merck and Co. Inc. (formerly Schering Plough and Organon), Moksha8, Naurex Inc., Neuronetics Inc., Novartis, Ortho-McNeil Pharmaceuticals (Johnson & Johnson; Janssen), Otsuka, Pamlab, L.L.C. (Nestle), Pfizer (formerly Wyeth Ayerst Pharmaceuticals), Shire US Inc., Sunovion Pharmaceuticals Inc., Trius Therapeutical Inc. and Takeda. Grant support: Agency for Healthcare Research and Quality, Alkermes, AssureRx, Avanir, Forest Pharmaceuticals, Janssen, National Institute of Mental Health, and Otsuka Pharmaceuticals. Speakers Bureau: None since June, 2010. Equity Holdings: MedAvante, Inc. Royalties: American Psychiatric Foundation, Guilford Publications, Herald House, W.W. Norton & Company, Inc. Spouse's employment: Peloton Advantage, which does business with Pfizer. M.T. Full-time employee at Lilly 1997 to 2008. Honoraria/consulted: Abbott, AstraZeneca, Bristol Myers Squibb, GlaxoSmithKline, Lilly, Johnson & Johnson, Allergan, Otsuka, Merck, Sunovion, Forest, Geodon Richter Plc, Roche, Elan, Alkermes, Lundbeck, Teva, Pamlab, Minerva, Wyeth and Wiley Publishing. Spouse was full time-employee at Lilly 1998-2013. © The Royal College of Psychiatrists 2016. This is an open access article distributed under the terms of the Creative Commons Non-Commercial, No Derivatives (CC BY-NC-ND) licence.

Enter the iPad (or Not?)

ERIC Educational Resources Information Center

Waters, John K.

2010-01-01

Few computing devices have sparked the burning gizmo lust ignited by the iPad. Apple's latest entry into the tablet PC market didn't generate much heat when it was first unveiled in January, but by April 3, the day of the official release, feverish customers were mobbing Apple stores. The company claims to have sold 300,000 iPads by midnight on…

Youthful Lust and Violation of Mobile Phone Rule in a Private Christian Mission University, South West Nigeria

ERIC Educational Resources Information Center

Ojo, Omonijo Dare; Ugochukwu, Nnedum Obiajulu Anthony; Obinna, Ezeokana Jude

2011-01-01

This study aims at discovering the difference in the perceived lack of privacy in communication and violation of mobile phone rule among students in a Private Christian Mission University, South-West Nigeria. It equally tries to discover if there is a difference in the perceived students' desire to express love to the opposite sex and violation of…

New application system for simultaneous laser and ultrasonic transmission in endoscopic surgery (LUST)

NASA Astrophysics Data System (ADS)

Desinger, Kai; Helfmann, Juergen; Stein, Thomas; Liebold, K.; Mueller, Gerhard J.

1998-04-01

A new combined Laser and Ultrasound Surgical Therapy (LUST) device for an endoscopically suitable coagulation and tissue fragmentation based on the transmission of laser radiation and ultrasound via flexible silica glass fibers was developed at the LMTB. The ultrasound tissue interaction is based on the well-known CUSA-technology, which enables the surgeon to cut various types of tissue with different degrees of effectiveness. This selective cutting performance is a very useful feature, e.g. for a brain tumor extirpation, where it must be guaranteed that vessels and nerves are not affected while ensuring a fast reduction of the tumor mass. Application fields are in oncology, neurosurgery and angioplasty. The laser radiation can be used for tissue coagulation purposes and homeostasis. With a fiber based LUST-system working at a resonance frequency of 30 kHz, using a laser-vibrometer, velocity amplitudes of up to 20 m/s could be detected at the distal end which corresponds to an elongation of more than 100 micrometers . The investigations have shown that the velocity amplitude, next to suction, frequency and cross section of the active fiber tip, has the greatest impact on the fragmentation rate. With a suction setting of 5 W, the following tissue fragmentation rates could be achieved with a 1.3 mm2 fiber cross section and a tip amplitude velocity of 12 m/s: brain tissue 50 mg/s, liver 4,5 mg/s and kidney 4 mg/s. Laser radiation up to 25 watt was sufficient to coagulate soft tissue. This new approach in developing an application system for the therapeutical use of laser radiation and ultrasound via optical waveguides offers new possibilities in minimally invasive surgery, providing a complete new working sphere for the surgeon. The flexible opto-acoustic waveguide (400 - 1700 micrometers ) can be bent making areas accessible which were inaccessible before. The surgeon can use the laser radiation for tissue coagulation or cutting and the ultrasound for tissue fragmentation and tissue reduction without changing the instrumentation.

Presidential Green Chemistry Challenge: 1999 Greener Synthetic Pathways Award

EPA Pesticide Factsheets

Presidential Green Chemistry Challenge 1999 award winner, Lilly Research Laboratories, developed a low-waste drug synthesis using yeast for a stereospecific reduction, reducing solvent amounts, and replacing chromium oxide.

"One-night stands" - risky trips between lust and trust: qualitative interviews with Chlamydia trachomatis infected youth in North Sweden.

PubMed

Christianson, Monica; Johansson, Eva; Emmelin, Maria; Westman, Göran

2003-01-01

The aim of the study was to get a deeper understanding of sexual risk-taking, by interviewing young people diagnosed with Chlamydia trachomatis. This qualitative study was conducted at a youth clinic in Umeå, Sweden. Five young women and four men, aged 18-22, participated. In-depth interviews were performed. Open questions around certain themes were posed, such as thoughts about getting CT, sexual encounters, and attitudes towards condoms. Interviews were tape-recorded and transcribed verbatim. Data were analysed according to grounded theory. Norms, events, and emotions were explored. The goal was to develop credible and applicable concepts concerning sexual relationships, risk-taking, and experiences of CT. Informants revealed that behind their sexual risk-taking was a drive to "go steady". Lust and trust were the guidelines if sex was going to take place. When discussing "one-night stands" gender stereotypes occurred. Females were expected to be less forward compared with males. We found an uneven distribution of responsibility concerning condoms. Males expected females to be "condom promoters". By catching CT, females experienced guilt, while males felt content through knowing "the source of contamination". An important public health issue is to implement how males should play an equal part in reproductive health. General CT screening of males is one suggestion.

Heart Failure Society of America

MedlinePlus

... HFSA News St. Luke’s Spotlights Critical Link Between Type 2 Diabetes and Heart Disease in Partnership with Boehringer Ingelheim and Eli Lilly and Company November 16, 2017 Allentown, PA, Nov. 14, 2017 – ...

For the relief of Lilly M. Ledbetter.

THOMAS, 111th Congress

Rep. Woolsey, Lynn C. [D-CA-6

2009-06-08

House - 06/15/2009 Referred to the Subcommittee on Immigration, Citizenship, Refugees, Border Security, and International Law. (All Actions) Tracker: This bill has the status IntroducedHere are the steps for Status of Legislation:

Conversation Currents: Learning from Families and Communities

ERIC Educational Resources Information Center

Compton-Lilly, Catherine; Gregory, Eve

2013-01-01

This column features two prominent literacy scholars, Catherine Compton-Lilly and Eve Gregory. They discuss their recent research studies in various contexts and describe the reciprocal relationships between school, home, and community literacy practices.

Ceroid in fish

USGS Publications Warehouse

Wood, E.M.; Yasutake, W.T.

1956-01-01

Since the original description of ceroid in rats, many papers have appeared on the etiology and characteristics of this pigment. It was first seen as a yellow, granular pigment in hematoxylin and eosin sections of the cirrhotic livers of choline deficient rats. The pigment was more fully characterized by Endicott and Lillie, and additional stainging reactions were summarized recently by Lillie. The pigment is sudanophilic in paraffin sections, acid-fast, basophilic, isotropic, iron negative, and highly resistant to solution in water, alcohol, fat solvents, and dilute aqueous acids and alkalis. It is stained by Mallory's hemofuscin stain and Weigert's myelin stain. It reduces osmium tetraoxide and diamine silver carbonate but not ferric ferricyanide. The Gmelin reactions for bile pigments is negative. It has a greenish yellow fluorescence at 3650-3660 Å. It is Schiff positive with or without antecedent diastase digestion after performic or periodic acid oxidation.

High heterogeneity and low reliability in the diagnosis of major depression will impair the development of new drugs.

PubMed

Lieblich, Samuel M; Castle, David J; Pantelis, Christos; Hopwood, Malcolm; Young, Allan Hunter; Everall, Ian P

2015-10-01

Major depressive disorder is a common diagnosis associated with a high burden of disease that has proven to be highly heterogeneous and unreliable. Treatments currently available demonstrate limited efficacy and effectiveness. New drug development is urgently required but is likely to be hindered by diagnostic limitations. D.J.C. has received grants and personal fees from Eli Lilly, Janssen-Cilag, Roche, Allergen, Bristol-Myers Squibb, Pfizer, Lundbeck, AstraZeneca, Hospira, Organon, Sanofi-Aventis, and Wyeth during the writing of this review. C.P. has received grant support from Janssen-Cilag, Eli Lilly, Hospira (Mayne), AstraZeneca, and received honoraria for consultancy to Janssen-Cilag, Eli Lilly, Hospira (Mayne), AstraZeneca, Pfizer, Schering Plough, and Lundbeck. Over the past 2 years he has participated on advisory boards for Janssen-Cilag and Lundbeck, and received honoraria for talks presented at educational meetings organised by AstraZeneca, Janssen-Cilag and Lundbeck. M.H. has received personal fees or grants from Lundbeck, AstraZeneca and Servier during the writing of this review. A.H.Y. reports personal fees from Lundbeck, Sunovion, AstraZeneca and Janssen outside the submitted work. I.P.E. has received personal fees or grants from Lundbeck, AstraZeneca, and Abbvie during the writing of this review. © The Royal College of Psychiatrists 2015. This is an open access article distributed under the terms of the Creative Commons Non-Commercial, No Derivatives (CC BY-NC-ND) licence.

The Proximal Lilly Collection: Mapping, Exploring and Exploiting Feasible Chemical Space.

PubMed

Nicolaou, Christos A; Watson, Ian A; Hu, Hong; Wang, Jibo

2016-07-25

Venturing into the immensity of the small molecule universe to identify novel chemical structure is a much discussed objective of many methods proposed by the chemoinformatics community. To this end, numerous approaches using techniques from the fields of computational de novo design, virtual screening and reaction informatics, among others, have been proposed. Although in principle this objective is commendable, in practice there are several obstacles to useful exploitation of the chemical space. Prime among them are the sheer number of theoretically feasible compounds and the practical concern regarding the synthesizability of the chemical structures conceived using in silico methods. We present the Proximal Lilly Collection initiative implemented at Eli Lilly and Co. with the aims to (i) define the chemical space of small, drug-like compounds that could be synthesized using in-house resources and (ii) facilitate access to compounds in this large space for the purposes of ongoing drug discovery efforts. The implementation of PLC relies on coupling access to available synthetic knowledge and resources with chemo/reaction informatics techniques and tools developed for this purpose. We describe in detail the computational framework supporting this initiative and elaborate on the characteristics of the PLC virtual collection of compounds. As an example of the opportunities provided to drug discovery researchers by easy access to a large, realistically feasible virtual collection such as the PLC, we describe a recent application of the technology that led to the discovery of selective kinase inhibitors.

A Comparison of Glide Force Characteristics Between 2 Prefilled Insulin Lispro Pens

PubMed Central

Lennartz, Amanda H.; Ignaut, Debra A.

2015-01-01

Background: Glide force, average glide force, and glide force variability of the insulin lispro 200 units/mL pen (Eli Lilly and Company, Indianapolis, IN, USA) were compared to the Humalog® KwikPen® 100 units/mL pen (hereafter, KwikPen; Eli Lilly and Company, Indianapolis, IN, USA). Methods: Data were collected on 2 doses, 2 injection speeds, and 2 needle types. Results: Insulin lispro 200 units/mL pen showed significantly lower maximum glide force, average glide force, and glide force variability than the KwikPen across all combinations of dose size, dose speed, and needle type. Conclusions: The lower glide force observed with the insulin lispro 200 units/mL pen offers another treatment option for patients with type 1 or type 2 diabetes who require greater than 20 units of mealtime insulin daily. PMID:25591858

Empowering the Community to Manage Diabetes Better: An Integrated Partnership-Based Model.

PubMed

Bamne, Arun; Shah, Daksha; Palkar, Sanjivani; Uppal, Shweta; Majumdar, Anurita; Naik, Rohan

2016-01-01

Rising number of diabetes cases in India calls for collaboration between the public and private sectors. Municipal Corporation of Greater Mumbai (MCGM) partnered with Eli Lilly and Company (India) [Eli Lilly] to strengthen the capacity of their diabetes clinics. Medical Officers, dispensaries and Assistant Medical Officers (AMOs) located at attached health posts were trained on an educational tool, Diabetes Conversation Map™ (DCM) by a Master Trainer. This tool was then used to educate patients and caregivers visiting the MCGM diabetes clinics. Twenty-eight centers conducted 168 sessions, and 1616 beneficiaries availed the education over six months. General feedback from health providers was that DCM helps clear misconceptions among patients and caregivers in an interactive way and also improves compliance of patients. This communication highlights a unique public-private partnership where the sincere efforts of public sector organization (MCGM) were complemented by the educational expertise lent by a private firm.

A more rational approach to new-product development.

PubMed

Bonabeau, Eric; Bodick, Neil; Armstrong, Robert W

2008-03-01

Companies often treat new-product development as a monolithic process, but it can be more rationally divided into two parts: an early stage that focuses on evaluating prospects and eliminating bad bets, and a late stage that maximizes the remaining candidates' market potential. Recognizing the value of this approach, Eli Lilly designed and piloted Chorus, an autonomous unit dedicated solely to the early stage. This article demonstrates how segmenting development in this way can speed it up and make it more cost-effective. Two classes of decision-making errors can impede NPD, the authors say. First, managers often ignore evidence challenging their assumptions that projects will succeed. As a result, many projects go forward despite multiple red flags; some even reach the market, only to fail dramatically after their introduction. Second, companies sometimes terminate projects prematurely because people fail to conduct the right experiments to reveal products' potential. Most companies promote both kinds of errors by focusing disproportionately on late-stage development; they lack the early, truth-seeking functions that would head such errors off. In segmented NPD, however, the early-stage organization maintains loyalty to the experiment rather than the product, whereas the late-stage organization pursues commercial success. Chorus has significantly improved NPD efficiency and productivity at Lilly. Although the unit absorbs just one-tenth of Lilly's investment in early-stage development, it delivers a substantially greater fraction of the molecules slated for late Phase II trials--at almost twice the speed and less than a third of the cost of the standard process, sometimes shaving as much as two years off the usual development time.

Environmental Baseline Survey Parcel E2, F, and I, Military Housing Areas Nellis Air Force Base, Nevada. Phase 1

DTIC Science & Technology

2011-09-01

SEP 2011 2. REPORT TYPE N/A 3. DATES COVERED - 4. TITLE AND SUBTITLE Final Phase I Environmental Baseline Survey Parcel E2, F, and I...lead-based paint LUST leaking underground storage tank M.D.M. Mount Diablo Meridian MFH military family housing MHPI Military Housing...northwest OWS oil/water separator PADS PCB Activity Database PCB polychorinated biphenyl PCR Physical Condition Report PDF portable

JPRS Report, Near East & South Asia

DTIC Science & Technology

1991-11-26

Jew can satisfy his lusts with the foreigner and his from Islam, no matter what the sacrifice costs, and no woman without restriction or limitation...usurped land is Palestine, and a non-Jewish woman or violates the honor of a foreign al-Aqsa mosque is the first of the two kiblahs [places girl, he...the consent of the fertilizers; increasing Egypt’s hard currency revenues; Soviet Union. I rule out the idea of a unipolar interna- providing job

76 FR 57719 - Procurement List; Additions

Federal Register 2010, 2011, 2012, 2013, 2014

2011-09-16

... Creek Recreation Area, 3211 Reservoir Road, Walla Walla, WA. NPA: Lillie Rice Center, Walla Walla, WA...: Warehouse Staffing Services, Warehouse Section--Building Branch--NOAA's Logistics Div., Building 22, 325... Desk (Call Center) Service, Defense Logistics Agency, Fort Belvoir, VA. (Offsite: 2511 Martin Luther...

75 FR 8720 - Ocean Transportation Intermediary License Applicants

Federal Register 2010, 2011, 2012, 2013, 2014

2010-02-25

... Logistics LLC, 6 Elna Ct., Bayonne, NJ 07002. Officer: Sameh F. Kaldes, President (Qualifying Individual...) Flash Forward Logistics Inc., 17 Sunset Avenue, Lynbrook, NY 11563. Officers: Lisa Chirichella, Treasurer (Qualifying Individual), Peter Chirichella, President Norton Lilly Logistics, LLC, One St. Louis...

Operation TEAPOT. Technical Summary of Military Effects, Programs 1-9

DTIC Science & Technology

1981-05-01

54 2.26 Dust dynami c pressure (,I( ) deorived from Greg, and Snob a.ir dynamic preo mu e (qa~) at 2,500.-foot...ration. An instrument designated as Greg was expected to respond to the total dy- lalmic pi ussure of !he air and the (lust, while the Snob ...the 3-foot Snob and Grtg ga cs gave abnormally low values again Inconsistent A ith other i’,.,trumentatIon. Although an interiediate value v.as l,o:sen

76 FR 16643 - NASA Advisory Council; Aeronautics Committee; Meeting

Federal Register 2010, 2011, 2012, 2013, 2014

2011-03-24

... NATIONAL AERONAUTICS AND SPACE ADMINISTRATION [Notice (11-024)] NASA Advisory Council; Aeronautics... Aeronautics and Space Administration announces a meeting of the Aeronautics Committee of the NASA Advisory.... ADDRESSES: Thursday, April 14, 2011--NASA Dryden Flight Research Center (DFRC), Lilly Drive Building 4825...

Hurricane Lilli

Atmospheric Science Data Center

2014-05-15

article title:  Hurricane Lili Heads for Louisiana Landfall     ... Image Characteristics of a strengthening Category 3 Hurricane Lili are apparent in these images from the Multi-angle Imaging ... (MISR), including a well-developed clearing at the hurricane eye. When these views were acquired on October 2, 2002, Lili was ...

75 FR 21232 - Application(s) for Duty-Free Entry of Scientific Instruments

Federal Register 2010, 2011, 2012, 2013, 2014

2010-04-23

... Institute, Kent State University, Summit Street, PO Box 5190, Kent, OH 44242. Instrument: Electron... W. State Street, Lilly Hall, B126, West Lafayette, IN 47907-2054. Instrument: Electron Microscope... viruses and other macromolecular assemblies. Using cryo-electron microscopy, numerous virus/macromolecular...

Empowering the Community to Manage Diabetes Better: An Integrated Partnership-Based Model

PubMed Central

Bamne, Arun; Shah, Daksha; Palkar, Sanjivani; Uppal, Shweta; Majumdar, Anurita; Naik, Rohan

2016-01-01

Context Rising number of diabetes cases in India calls for collaboration between the public and private sectors. Aims: Municipal Corporation of Greater Mumbai (MCGM) partnered with Eli Lilly and Company (India) [Eli Lilly] to strengthen the capacity of their diabetes clinics. Materials and Methods Medical Officers, dispensaries and Assistant Medical Officers (AMOs) located at attached health posts were trained on an educational tool, Diabetes Conversation Map™ (DCM) by a Master Trainer. This tool was then used to educate patients and caregivers visiting the MCGM diabetes clinics. Results Twenty-eight centers conducted 168 sessions, and 1616 beneficiaries availed the education over six months. General feedback from health providers was that DCM helps clear misconceptions among patients and caregivers in an interactive way and also improves compliance of patients. Conclusions This communication highlights a unique public-private partnership where the sincere efforts of public sector organization (MCGM) were complemented by the educational expertise lent by a private firm. PMID:27051094

Positioning laboratory automation for today's dynamic climate

PubMed Central

Vogt, D. G.

1994-01-01

Laboratory automation has existed and matured at Eli Lilly and Company for well over a decade. The author's section serves as a developer of laboratory automation systems for customers within Lilly and embodies ‘robotic friendly’ laboratories with highly technical and experienced personnel. With several systems showing signs of age, second generation ‘smart systems’ have been developed and delivered during the last three years. These systems were built with an ideology different from previous systems. Upon their delivery, the ‘smart systems’ met the customer's functional requirements but the overall acceptance of this ideology is still being debated due to the perception of failure. Much of this perception can be attributed to the delivery of a system heavily dependent on system maintenance, something totally unexpected by the customer. This paper discusses the ideology of a‘smart systems’ and the results following implementation. The events that led to the review and subsequent departure of the ‘smart systems’ ideology are also described. PMID:18924995

Worm Disease Profile of Primary School Children

NASA Astrophysics Data System (ADS)

Hartati; Destriani; Victoria, A. R.

2018-01-01

The result of an elementary study of relations between disease symptoms and signs with the wormy occurrence child at Elementary School in Ilir Barat II Subdistrict of Palembang in concerned in this research amount to 200 people from the population of 4200 people of a child in elementary school. The result indicates that the child roommates infested worm marked with a few symptoms like passion eat to Decrease the puking pain in the home of stomach after eating, diarrhea, defecate with the mucus and bleed the purities at the anus before controlled from some worm type of there no difference having a meaning between child roommates worm infested with the child roommates do not infest worm (P > 0.05). Symptom vomit got more amount by having a meaning a child by infested is Trichuris (RO > 2.669, P < 0/005). The result of infested Tricuris generate the more amount of symptoms lust to eat to Decrease by having a meaning of Compared to the which do not infest Trichuris (RO = 3.772; CI 95% = 1.214 to 11.726; P = 0.016) symptoms lust to eat to Decrease and more amount diarrhea got at Infest oxyuris with the special sign of purities at nighttime anus (RO = 0.557; 85% CI = 0.166 to 2.168). The risk of the happening of unfavorable nutrition According to BB / U and Also TB / U growing niche to more amount (having a meaning) at child roommates worm infested by a child Compared to the which do not infest worm.

The Law of Communicable Diseases Act and disclosure to sexual partners among HIV-positive youth.

PubMed

Christiansen, Monica; Lalos, Ann; Johansson, Eva E

2008-12-01

In Sweden, human immunodeficiency virus (HIV) is included among the venereal diseases covered by the Law of Communicable Diseases Act. HIV-positive (HIV(+)) people are required to inform their sexual partners about their infection and adopt safe sex behaviours. However, it is unclear how the law is perceived. This study explores how HIV(+) youth in Sweden perceive the law, handle their sexuality and disclose their HIV diagnosis to sexual partners. Ten HIV(+) women and men between 17 and 24 years of age were recruited from three different HIV infection clinics. These participants were interviewed in depth. The interviews were tape-recorded, transcribed verbatim and analysed according to a grounded theory approach. The core category-cultured to take responsibility-illuminates the informants' double-edged experiences regarding the law and how they handle disclosure to sexual partners. The legislation implies both support and burden for these HIV(+) youth; they feel that they have a great deal of responsibility, sometimes more than they can handle. 'Switch off lust', 'balancing lust, fear and obedience' and 'switch off the disease' are strategies that describe how the informants manage sexuality and disclosure. Young HIV(+) people have a difficult time informing partners of their HIV diagnosis and discussing safe sex strategies. These are challenges that health care providers need to take seriously. HIV(+) youth need better communication strategies to negotiate safer sex. Staff with extended education on sexuality should be a part of HIV health care.

Flexible Design and Manufacturing Systems for Automotive Components and Sheet Metal Parts

DTIC Science & Technology

1999-10-01

sometimes shocking discoveries you will make, discoveries that can help you avoid potential crises down the road if you take the necessary steps now...ISSUE Guest Lecture John Swanson, VP Qualcomm 10-Feb Fast, Flexible, Lilly, US Robotics, Economist, Upton & Agile Manufacturing Readings

Decisionmaker Forums

DTIC Science & Technology

2005-03-01

Committee professional staff, Brian Hurley of Edward Martin & Associates, Michael Kussman of the VA, Steve Lillie of DoD, Steve Mirick ofAMSUSBob...Michael Kussman of VHA; Bruce Levine of VHA; Miklos Losonczy of VHA; Susan Mather of VHA; Theodore Nam of DoD; Harold Wain of DoD; Terry Washam of

Prasugrel (Effient) vs. clopidogrel (Plavix).

PubMed

2009-09-07

The FDA has approved prasugrel (Effient--Lilly/Daiichi Sankyo), an oral antiplatelet drug, for use with aspirin to reduce the rate of thrombotic cardiovascular events in patients with acute coronary syndromes (ACS) being managed with percutaneous coronary intervention (PCI).1 It will compete with clopidogrel (Plavix) for such use.

Alterations in dorsal and ventral posterior cingulate connectivity in APOE ε4 carriers at risk of Alzheimer's disease.

PubMed

Kerestes, Rebecca; Phal, Pramit M; Steward, Chris; Moffat, Bradford A; Salinas, Simon; Cox, Kay L; Ellis, Kathryn A; Cyarto, Elizabeth V; Ames, David; Martins, Ralph N; Masters, Colin L; Rowe, Christopher C; Sharman, Matthew J; Salvado, Olivier; Szoeke, Cassandra; Lai, Michelle; Lautenschlager, Nicola T; Desmond, Patricia M

2015-10-01

Recent evidence suggests that exercise plays a role in cognition and that the posterior cingulate cortex (PCC) can be divided into dorsal and ventral subregions based on distinct connectivity patterns. To examine the effect of physical activity and division of the PCC on brain functional connectivity measures in subjective memory complainers (SMC) carrying the epsilon 4 allele of apolipoprotein E (APOE ε 4) allele. Participants were 22 SMC carrying the APOE ε 4 allele ( ε 4+; mean age 72.18 years) and 58 SMC non-carriers ( ε 4-; mean age 72.79 years). Connectivity of four dorsal and ventral seeds was examined. Relationships between PCC connectivity and physical activity measures were explored. ε 4+ individuals showed increased connectivity between the dorsal PCC and dorsolateral prefrontal cortex, and the ventral PCC and supplementary motor area (SMA). Greater levels of physical activity correlated with the magnitude of ventral PCC-SMA connectivity. The results provide the first evidence that ε 4+ individuals at increased risk of cognitive decline show distinct alterations in dorsal and ventral PCC functional connectivity. D.A. has served on scientific advisory boards for Novartis, Eli Lilly, Janssen, Prana and Pfizer, and as Editor-in-Chief for International Psychogeriatrics; received speaker honoraria from Pfizer and Lundbeck, and research support from Eli Lilly, GlaxoSmithKline, Forest Laboratories, Novartis, and CSIRO. C.L.M. has received consulting fees from Eli Lilly and Prana Biotechnology, and has stock ownership in Prana Biotechnology. C.C.R. has received consultancy payments from Roche and Piramal, and research support from Avid Radiopharmaceuticals, Eli Lilly, GE Healthcare, Piramal and Navidea for amyloid imaging. C.S. has provided clinical consultancy and been on scientific advisory committees for the Australian CSIRO, Alzheimer's Australia, University of Melbourne and other relationships, which are subject to confidentiality clauses; she has been a named Chief Investigator on investigator-driven collaborative research projects in partnership with Pfizer, Merck, Piramal, Bayer and GE Healthcare. Her research programme has received support from the National Health and Medical Research Council Alzheimer's Association, Collier Trust, Scobie and Claire McKinnon Foundation, JO and JR Wicking Trust, Shepherd Foundation, Brain Foundation, Mason Foundation, Ramaciotti Foundation, Alzheimer's Australia and the Royal Australian College of Physicians. © The Royal College of Psychiatrists 2015. This is an open access article distributed under the terms of the Creative Commons Non-Commercial, No Derivatives (CC BY-NC-ND) licence.

Alterations in dorsal and ventral posterior cingulate connectivity in APOE ε4 carriers at risk of Alzheimer's disease

PubMed Central

Phal, Pramit M.; Steward, Chris; Moffat, Bradford A.; Salinas, Simon; Cox, Kay L.; Ellis, Kathryn A.; Cyarto, Elizabeth V.; Ames, David; Martins, Ralph N.; Masters, Colin L.; Rowe, Christopher C.; Sharman, Matthew J.; Salvado, Olivier; Szoeke, Cassandra; Lai, Michelle; Lautenschlager, Nicola T.; Desmond, Patricia M.

2015-01-01

Background Recent evidence suggests that exercise plays a role in cognition and that the posterior cingulate cortex (PCC) can be divided into dorsal and ventral subregions based on distinct connectivity patterns. Aims To examine the effect of physical activity and division of the PCC on brain functional connectivity measures in subjective memory complainers (SMC) carrying the epsilon 4 allele of apolipoprotein E (APOE ε4) allele. Method Participants were 22 SMC carrying the APOE ε4 allele (ε4+; mean age 72.18 years) and 58 SMC non-carriers (ε4–; mean age 72.79 years). Connectivity of four dorsal and ventral seeds was examined. Relationships between PCC connectivity and physical activity measures were explored. Results ε4+ individuals showed increased connectivity between the dorsal PCC and dorsolateral prefrontal cortex, and the ventral PCC and supplementary motor area (SMA). Greater levels of physical activity correlated with the magnitude of ventral PCC–SMA connectivity. Conclusions The results provide the first evidence that ε4+ individuals at increased risk of cognitive decline show distinct alterations in dorsal and ventral PCC functional connectivity. Declaration of interest D.A. has served on scientific advisory boards for Novartis, Eli Lilly, Janssen, Prana and Pfizer, and as Editor-in-Chief for International Psychogeriatrics; received speaker honoraria from Pfizer and Lundbeck, and research support from Eli Lilly, GlaxoSmithKline, Forest Laboratories, Novartis, and CSIRO. C.L.M. has received consulting fees from Eli Lilly and Prana Biotechnology, and has stock ownership in Prana Biotechnology. C.C.R. has received consultancy payments from Roche and Piramal, and research support from Avid Radiopharmaceuticals, Eli Lilly, GE Healthcare, Piramal and Navidea for amyloid imaging. C.S. has provided clinical consultancy and been on scientific advisory committees for the Australian CSIRO, Alzheimer's Australia, University of Melbourne and other relationships, which are subject to confidentiality clauses; she has been a named Chief Investigator on investigator-driven collaborative research projects in partnership with Pfizer, Merck, Piramal, Bayer and GE Healthcare. Her research programme has received support from the National Health and Medical Research Council Alzheimer's Association, Collier Trust, Scobie and Claire McKinnon Foundation, JO and JR Wicking Trust, Shepherd Foundation, Brain Foundation, Mason Foundation, Ramaciotti Foundation, Alzheimer's Australia and the Royal Australian College of Physicians. Copyright and usage © The Royal College of Psychiatrists 2015. This is an open access article distributed under the terms of the Creative Commons Non-Commercial, No Derivatives (CC BY-NC-ND) licence. PMID:27703739

76 FR 4868 - Availability of Seats for the Florida Keys National Marine Sanctuary Advisory Council

Federal Register 2010, 2011, 2012, 2013, 2014

2011-01-27

... CONTACT: Lilli Ferguson, Florida Keys National Marine Sanctuary, 33 East Quay Rd., Key West, FL 33040... the Florida Keys National Marine Sanctuary Advisory Council AGENCY: Office of National Marine... applications for the following vacant positions on the Florida Keys National Marine Sanctuary Advisory Council...

Beyond "It Was Great"? Not so Fast!

ERIC Educational Resources Information Center

Wong, E. David

2015-01-01

The Forum on Education Abroad's Ninth Annual Conference in 2013 was organized around the provocative theme, "Moving Beyond It Was Great." In the opening plenary speech, Lilli Engle warned the audience of study abroad researchers, leaders, administrators, and providers that study abroad programs were not as effective as they may want to…

School outreach event

NASA Image and Video Library

2012-01-27

Freddie Douglas, manager of the Stennis Office of Safety and Mission Assurance, joins students to watch a robotic demonstration during activities at Lillie Burney Elementary School in Hattiesburg, Miss., on Jan. 27, 2012. NASA senior staff members from Stennis Space Center visited the school for a morning of activities and outreach to students and school officials.

2006 Land and Maritime Supply Chains Business Conference and Exhibition

DTIC Science & Technology

2006-08-30

404 Patterson Fan Company.................................602 PDA, LLC........................................................303...210 TW Design & Manufacturing...........................616 Vermont Aerospace Manufacturing.................402 WW Williams ... William M. Lenaers, USA Commanding General, US Army TACOM “What Your Largest Customer Thinks” 1:55pm - Remarks 2:15pm Rear Admiral Charlie M. Lilli

Networked Success and Failure at Hybritech

ERIC Educational Resources Information Center

Jones, Mark Peter

2011-01-01

The author presents an historical account of scientific work conducted at a commercial biotech firm in San Diego called Hybritech. It tells of disruptions in research programs following the acquisition of the company by the pharmaceutical giant Eli Lilly in 1986. The story centers on responses to an organizational challenge that research managers…

Drug Advertising and the FDA.

ERIC Educational Resources Information Center

Levesque, Cynthia

With increases in consumer focused advertising for prescription drugs, the Federal Drug Administration has renewed efforts to protect the public from false advertising. In 1982, it charged that the press kits Eli Lilly and Company distributed to reporters on its new antiarthritis drug, Oraflex, misrepresented the product. It recommended that Lilly…

Lesson Plans on African History and Geography: A Teaching Resource.

ERIC Educational Resources Information Center

Hamilton, Robert E., Ed.

This document presents lesson plans for instruction concerning the history and geography of the continent of Africa. Topics include: (1) "The Challenge of Teaching African History and Culture" (Robert Hamilton); (2) "A Physical Overview of Africa" (Robert Hamilton and Kim Lilly); (3) "A Cultural Overview of Africa"…

Democracy and Deterrence: Foundations for an Enduring World Peace

DTIC Science & Technology

2008-05-01

Sigmund Freud , in his corre- spondence with Albert Einstein later published as Why War?, asserts that “man has within himself a lust for hatred and de...template.cfm?page=47&nit=342&year=2004. –––––. The World’s Most Repressive Regimes. Washington, DC: Freedom House, 2003. Freud , Sigmund . To Albert...136, 144, 146, 151 freedom of religion, ix, 3–6, 45, 56, 87, 128, 131, 136, 144, 146, 151 freedom of speech, 45, 54, 56, 67–68, 83 Freud , Sigmund , 22

The Tides of Tradition: Culture and Reform at the University of Alabama.

ERIC Educational Resources Information Center

Alabama Univ., Birmingham.

This collection serves as an interpretation of traditions, rituals, legacies, and the historical challenges associated with the University of Alabama. As such, it is a consolidated historical record of the cultural history of the university. The chapters are: (1) "Introduction" (Chad Caples, Lillie Hagood, Kurt Johnson, Anne Kanga, Julie…

More Top Students Answer the Ministry's Call

ERIC Educational Resources Information Center

Supiano, Beckie

2008-01-01

In an effort to help reverse a decades-long decline in the number of top students entering seminaries, the Lilly Endowment invited colleges to compete for grants to be used for three related purposes: (1) to help students explore the relationship between faith and work; (2) to encourage talented students to consider entering Christian ministry;…

Seizure Risk in Patients with Attention-Deficit-Hyperactivity Disorder Treated with Atomoxetine

ERIC Educational Resources Information Center

Wernicke, Joachim F.; Holdridge, Karen Chilcott; Jin, Ling; Edison, Timothy; Zhang, Shuyu; Bangs, Mark E.; Allen, Albert J.; Ball, Susan; Dunn, David

2007-01-01

The comorbidity of seizures, epilepsy, and attention-deficit-hyperactivity disorder (ADHD) prompted the examination of whether atomoxetine use for ADHD is associated with an increased risk of seizures. Seizures and seizure-related symptoms were reviewed from two independent Eli Lilly and Company databases: the atomoxetine clinical trials database…

An Education for Life Abundant

ERIC Educational Resources Information Center

Roels, Shirley J.

2014-01-01

In the late 1990s, the wild hope of the Lilly Endowment was that a set of American higher education institutions would respond to the call for an exploration of vocation, giving a portion of their precious institutional lives to explore this question with undergraduates. Through projects on multiple campuses, the intent was to learn whether and…

76 FR 76894 - New Animal Drugs for Use in Animal Feeds; Tilmicosin

Federal Register 2010, 2011, 2012, 2013, 2014

2011-12-09

.... FDA-2011-N-0003] New Animal Drugs for Use in Animal Feeds; Tilmicosin AGENCY: Food and Drug... Elanco Animal Health, a division of Eli Lilly & Co. The supplemental NADA provides for use of tilmicosin..., Indianapolis, IN 46285, filed a supplement to NADA 141-064 for PULMOTIL 90 (tilmicosin phosphate) Type A...

UTEP: Urban Teacher Education Program. Final Report to the Lilly Endowment On Program Evaluation.

ERIC Educational Resources Information Center

Sandoval, Pamela A.

The Urban Teacher Education Program (UTEP) is a project of Indiana University Northwest (IUN) and three urban school districts (Gary, East Chicago, and Hammond, Indiana) to develop novice teachers, continue professional development among experienced professionals, and provide a forum for research on teacher education. Following discussion of the…

The Costs and Benefits of Deferred Giving.

ERIC Educational Resources Information Center

Fink, Norman S.; Metzler, Howard C.

It is argued in this book that while there can be a significant payoff for deferred giving programs, it is important to determine their cost effectiveness. Modern business methods of cost accounting, benefits analysis, and actuarial and econometric forecasting are applied to the Pomona College plan, whose study was supported by Lilly Endowment,…

Promotion of Critical Thinking in Clinical Nursing Post Conferences: A Peer Interactive Approach

ERIC Educational Resources Information Center

Stevens, Joanne

2009-01-01

Several workshops presented at the 2005 Lilly Conference on College Teaching in Oxford, Ohio, provided the inspiration for redesigning the clinical post conference for a foundational nursing course. Given the complexity and acuity of patient conditions today, fostering critical thinking in student nurses is central to quality patient care. The…

Recommended Policies and Practices for Advancing Indiana's System of Adult Education and Workforce Training

ERIC Educational Resources Information Center

National Center for Higher Education Management Systems (NJ1), 2009

2009-01-01

With generous support from the Lilly Endowment, the Indiana Chamber has contracted with National Center for Higher Education Management Systems (NCHEMS) to provide a policy framework and specific recommendations for improving the system of adult education and workforce training in Indiana--building on the important initiatives that have already…

Language Policy Processes and Consequences: Arizona Case Studies

ERIC Educational Resources Information Center

Moore, Sarah C. K., Ed.

2014-01-01

This book traces the recent socio-historical trajectory of educational language policy in Arizona, the state with the most restrictive English-only implementation in the United States. Chapters, each representing a case study of policy-making in the state, include: (1) SEI in Arizona: Bastion for States' Rights (Karen E. Lillie and Sarah Catherine…

Academic Literacies and Systemic Functional Linguistics: How Do They Relate?

ERIC Educational Resources Information Center

Coffin, Caroline; Donohue, James P.

2012-01-01

Two approaches to English for Academic Purposes (EAP) research and teaching which have arisen in recent years are systemic functional linguistics (SFL) approaches in Australia and elsewhere (e.g. Hood, 2006; Lee, 2010; Woodward-Kron, 2009) and Academic Literacies approaches in the UK and elsewhere (e.g. Lillis & Scott, 2008; Thesen &…

The Ripple Effect: Lessons from a Research and Teaching Faculty Learning Community

ERIC Educational Resources Information Center

Hershberger, Andrew; Spence, Maria; Cesarini, Paul; Mara, Andrew; Jorissen, Kathleen Topolka; Albrecht, David; Gordon, Jeffrey J.; Lin, Canchu

2009-01-01

Building upon a related 2005 panel presentation at the 25th annual Lilly Conference on College Teaching, Miami University, Oxford, Ohio, the authors, several tenure-track assistant professors and tenured associate professors who have participated in a Research and Teaching Faculty Learning Community at Bowling Green State University, share their…

BAAL/CUP Seminars 2013/Text Trajectories--Developing Dynamic Approaches to Textual Analysis

ERIC Educational Resources Information Center

Maybin, Janet; Lillis, Theresa

2015-01-01

This seminar took place on 19 April, 2013 at the Centre for Language and Communication, Faculty of Language and Education Studies, The Open University. The seminar was coordinated by Janet Maybin and Theresa Lillis and there were 28 participants, including four postgraduate students, from universities in Britain, Belgium and South Africa.

A Report from the Mid-America Program 1974-1978.

ERIC Educational Resources Information Center

Social Studies Development Center, Bloomington, IN.

The Mid-America Program for Global Perspectives in Education (MAP) was developed to prepare global curriculum materials, hold conferences for teachers, cooperate with other educational agencies, and help educational programs adjust to realities of a fast-changing world. Initiated in 1974 with a grant from the Lilly Foundation to the Social Studies…

VizieR Online Data Catalog: The Canada-France Redshift Survey (CFRS) (Lilly+, 1995)

NASA Astrophysics Data System (ADS)

Lilly, S. J.; Le Fevre, O.; Crampton, D.; Hammer, F.; Tresse, L.

2001-11-01

The Canada-France Redshift Survey (CFRS) is a collaboration between astronomers in Canada and France: Simon Lilly (University of Toronto), Olivier Le Fevre and Francois Hammer (Observatoire de Paris Meudon), David Crampton (Dominion Astrophysical Observatory, Victoria), Laurence Tresse (Cambridge University), and David Schade and Dan Hudon (University of Toronto). The survey is based primarily on observations with the 3.6m Canada-France-Hawaii Telescope (CFHT) on Mauna Kea, Hawaii. The CFRS consists of spectra of over 1000 faint objects selected to have 17.5 < I(AB) < 22.5 in five regions of sky. The survey is providing the first systematic study of normal galaxies at redshifts z > 0.5, corresponding to look-back times of greater than 50% of the age of the Universe. Observations of CFRS galaxies have also been made with the Hubble Space Telescope and the survey will form the basis of future studies with a number of other ground-based and space facilities. We have written a lay-persons guide to the CFRS and the main scientific results that are emerging from it. (1 data file).

Ehlers-Danlos syndrome and wound healing: injury in a collagen disorder.

PubMed

Trudgian, Julie; Trotman, Sara

Ehlers-Danlos syndrome (EDS) is a rare familial disorder affecting the production, quality and strength of collagen. It presents in many forms, and many individuals experience hypermobile joints and soft, elastic skin. When injury occurs, EDS can result in severe bruising, the development of wide open wounds and delayed healing (Babak et al, 2003). In the case discussed, Lilly, a 10-year-old girl, presented with a wide trauma injury to her lower leg. Healing was influenced by the poor collagen production associated with EDS, and the presence of a high bacterial burden that resulted in infection. Manuka honey was used to reduce the level of invading bacilli and stimulate production of collagen. Following this intervention, complete healing was achieved in two weeks. The action of manuka honey appears to be beneficial in the management of complex wounds, and further research is needed to determine its value in EDS. Involvement of Lilly and her family in clinical decision-making and in the production of this article resulted in a growth in understanding for all parties and the development of a relationship that optimized the nurse/patient experience.

Specific Reaction Patterns to Distinct Positive Emotional Cues Related to Incentive Motivation in Dependence of the Taq1A-Polymorphism: Molecular Genetic Associations of Early and Late Event-Related Potentials.

PubMed

Munk, Aisha J L; Wielpuetz, Catrin; Osinsky, Roman; Müller, Erik M; Grant, Phillip; Hennig, Jürgen

2016-01-01

Early and late event-related potential (ERP) responses, representing early subconscious and late motivational processes, were recorded for positive emotional words related to 'wanting' and 'liking', in dependence of the dopamine-related Taq1A genotype (ANKK1/DRD2). Research suggests that 'wanting' as opposed to 'liking' is related to dopaminergic processes. Therefore, it was hypothesized that risk allele carriers of the Taq1A polymorphism exhibit late ERP changes in reaction to words representing incentive motivation, i.e. 'wanting' (word categories 'lust' and 'anticipation'), but not to words representing 'liking' ('closeness'). Seventy-two male participants performed an emotional-word Stroop task during EEG recording and were genotyped according to the Taq1A polymorphism of ANKK1/DRD2. Positive emotional words related to anticipation and lust revealed blunted responses in the late positive potential (LPP) in carriers of the A1 allele, an effect absent in response to 'liking'-related words. These differences were not evident in the earlier posterior negativity (EPN). As no differences in dependence of the Taq1A genotype were observed in reaction to 'wanting'- and 'liking'-related words in the EPN, but merely in the LPP, it can be assumed that incentive-motivational stimuli only modify motivation-related ERP responses in carriers of the A1 allele of the Taq1A polymorphism, indicating the role of dopamine in late ERP components. © 2016 S. Karger AG, Basel.

"Back-fire to lust": G. Stanley Hall, sex-segregated schooling, and the engine of sublimation.

PubMed

Graebner, William

2006-08-01

G. Stanley Hall was an advocate of sex-segregated schooling long after most Americans had accepted coeducation. His position was based in part on personal experience: observations of his father and mother, a repressed and guilt-ridden boyhood sexuality, and his conviction that his own career success was a product of sublimated sexual desire, of erotic energy converted into mental energy. Hall theorized that coeducation put sublimation at risk, and that sex-segregated schools, by contributing to proper gendered development and by prolonging and sublimating the sexual tensions of adolescence, would produce social progress.

Man-boy lovers: assessment, counseling, and psychotherapy.

PubMed

van Naerssen, A

1990-01-01

Clinical experiences with 36 males, between the ages of 21 and 60 are described. All of them felt an enduring sexual attraction for boys. Sixteen males were treated for sexual identity conflicts. For eight of them this ended in a positive self-labeling as pedophile, the others had severe problems with accepting sexuality as positive and lustful. Twenty males were treated for identity management problems and counseled how to handle their relationships with boys. Several modalities of interpersonal interaction in man-boy relationships are proposed and the ways conflicts can arise within these frames of reference are explored in counseling and psychotherapy.

Nielsen's Little Room: Its Uses with a Young Blind and Physically Disabled Girl.

ERIC Educational Resources Information Center

Dunnett, J.

1997-01-01

Describes equipment, developed by the Danish teacher-therapist Lilli Nielsen, that was used with a 3-year-old child with blindness who was showing no sign of independent spontaneous movement while at nursery school. Explains the use of a resonance board and a Little Room, equipped with a variety of interesting objects. (Author/CR)

Interactions among Gift-Aid Programs in Indiana.

ERIC Educational Resources Information Center

Klein, Stephen P.; And Others

A study was done of the Lilly Endowment Educational Awards (LEEAs), one type of gift-aid for fulltime undergraduate Indiana residents. In particular the study addressed: (1) who receives LEEAs; (2) how Pell, State of Indiana, and LEEA formulas interact; (3) what happens when LEEAs are combined with all of the other types of gift-aid for a total…

Publications - GMC 423 | Alaska Division of Geological & Geophysical

Science.gov Websites

and Facilities Staff Seismic and Well Data Data Reports Contact Us Frequently Asked Questions Ask a Sheep Creek 1 well, Susitna basin, south-central Alaska Authors: Stanley, R.G., Lillis, P.G., Pawlewicz and is provided here as standard procedure for GMC sample agreements as well as an added value to our

A Long Island Consortium Takes Shape. Occasional Paper No. 76-1.

ERIC Educational Resources Information Center

Taylor, William R.

This occasional paper, the first in a "new" series, describes the background, activities, and experiences of the Long Island Consortium, a cooperative effort of two-year and four-year colleges committed to organizing a model program of faculty development. The consortium was organized under an initial grant from the Lilly Endowment. In May and…

Putting Resources into Practice: A Nexus Analysis of Knowledge Mobilisation Activities in Language Research and Multilingual Communities

ERIC Educational Resources Information Center

Pietikäinen, Sari; Compton, Sarah E.; Dlaske, Kati

2015-01-01

Recent demand within the academy for language research that bridges different stakeholders renders the social relevance of research a factor in the academic competition for research funds [Curry, M. J., & Lillis, T. (2013). "Introduction to the thematic issue: Participating in academic publishing--consequences of linguistic policies and…

Some Thoughts on English for Research Publication Purposes (ERPP) and Related Issues

ERIC Educational Resources Information Center

Flowerdew, John

2015-01-01

Academic writing for research publication takes place around the globe, involving, according to a recent account, 5.5 million scholars, 2,000 publishers and 17,500 research/higher education institutions (Lillis & Curry 2010: 1). Because so many scholars whose first language is not English are now using English for publication purposes and…

Selected Papers from the National Conference on College Teaching and Learning (7th, Jacksonville, Florida, March 20-23, 1996).

ERIC Educational Resources Information Center

Chambers, Jack A., Ed.

This collection of 20 papers is centered on the theme "Teaching, Learning, and Technology--Strategies to Motivate Life Long Learning." Titles include: (1) "Barriers to Effective Teamwork and Recommendations for Solutions" (Lillie Anderton-Lewis and Danny H. Pogue); (2) "Are Group Rewards Necessary for Cooperative Learning?…

National Technical Assistance Systems in Special Education.

ERIC Educational Resources Information Center

Reynolds, Maynard C., Ed.

Presented are 17 papers and a summary from the 1974 conference on National Technical Assistance Systems in Special Education. Included are presentations by the following participants: J. Gallagher, D. Stedman, D. Lillie and T. Black, D. Davies, E. Deno, J. McCarthy, D. Jackson, K. Lundholm, J. Chalfant, R. Johnson et al., P. Mann, W. Korba, R.…

Language Ideology Change over Time: Lessons for Language Policy in the U.S. State of Arizona and Beyond

ERIC Educational Resources Information Center

Fitzsimmons-Doolan, Shannon

2018-01-01

In the U.S. state of Arizona, language minority students who are English learners attend schools governed by a restrictive medium of instruction (MOI) language policy (LP). Educators and educational researchers widely agree that effective reforms of this policy are urgently needed (e.g., Arias & Faltis, 2012; Lawton, 2012; Lillie, 2016).…

Proceedings of the Annual Meeting of the Association for Education in Journalism and Mass Communication (80th, Chicago, Illinois, July 30-August 2, 1997): Media and Disability.

ERIC Educational Resources Information Center

Association for Education in Journalism and Mass Communication.

The Media and Disability section of the Proceedings contains the following eight papers: "Disability Publication Demographics and Coverage Models" (Lillie S. Ransom); "Franklin Delano Roosevelt and His Disability: The 'Chicago Tribune' and the 1936 Election" (Darlene Jirikowic); "A Search for Indications of Disability…

A Family Case Study: How Money Might Matter for Academic Learning

ERIC Educational Resources Information Center

Compton-Lilly, Catherine

2014-01-01

Many children living in low-income communities do not face struggles in school. Many learn quickly and easily. But for some students, living in a high poverty communities and attending underfunded schools has consequences that can make learning difficult. In this paper, Compton-Lilly draws on the words of a parent living in a low-income community…

Reading Time: The Literate Lives of Urban Secondary Students and Their Families. Language & Literacy Series

ERIC Educational Resources Information Center

Compton-Lilly, Catherine

2012-01-01

While teachers cannot travel back in time to visit their students at earlier ages, they can draw on the rich sets of experiences and knowledge that students bring to classrooms. In her latest book, Catherine Compton-Lilly examines the literacy practices and school trajectories of eight middle school students and their families. Through a unique…

Practicing a Good Life: Three Case Studies from the Programs for the Theological Exploration of Vocation

ERIC Educational Resources Information Center

Sutphen, Molly

2014-01-01

The Lilly Endowment's Programs for the Theological Exploration of Vocation offered a range of educational activities and opportunities for students, faculty, and staff to reflect on and discern their values, beliefs, and goals across a wide spectrum of collegiate life. Tim Clydesdale has found that these opportunities were of much value to those…

Report on Project Access Research

DTIC Science & Technology

1989-06-30

University), Kenneth M. Hoffman (Professor of Mathematics, MIT), Matina Horner (President, Radcliffe College), Lilli S. Hornig (Higher Education Resource...cover letter kindly provided by Radcliffe College President Matina Horner , who signed each letter. PA-I questionnaire was sent to 11 former Science...young female scientists who have been members of the Bunting Institute at Radcliffe (and its predecessor, the Radcliffe Institute), serving thereby also

Continuous flow technology vs. the batch-by-batch approach to produce pharmaceutical compounds.

PubMed

Cole, Kevin P; Johnson, Martin D

2018-01-01

For the manufacture of small molecule drugs, many pharmaceutical innovator companies have recently invested in continuous processing, which can offer significant technical and economic advantages over traditional batch methodology. This Expert Review will describe the reasons for this interest as well as many considerations and challenges that exist today concerning continuous manufacturing. Areas covered: Continuous processing is defined and many reasons for its adoption are described. The current state of continuous drug substance manufacturing within the pharmaceutical industry is summarized. Current key challenges to implementation of continuous manufacturing are highlighted, and an outlook provided regarding the prospects for continuous within the industry. Expert commentary: Continuous processing at Lilly has been a journey that started with the need for increased safety and capability. Over twelve years the original small, dedicated group has grown to more than 100 Lilly employees in discovery, development, quality, manufacturing, and regulatory designing in continuous drug substance processing. Recently we have focused on linked continuous unit operations for the purpose of all-at-once pharmaceutical manufacturing, but the technical and business drivers that existed in the very beginning for stand-alone continuous unit operations in hybrid processes have persisted, which merits investment in both approaches.

Identification of N-Terminally Truncated Derivatives of Insulin Analogs Formed in Pharmaceutical Formulations.

PubMed

Zielińska, Joanna; Stadnik, Jacek; Bierczyńska-Krzysik, Anna; Stadnik, Dorota

2018-05-16

Isolation and identification of unknown impurities of recombinant insulin lispro (produced at IBA) formed during accelerated stability testing of pharmaceutical solutions. For comparative purposes also commercially available formulations of recombinant human insulin (Humulin S®; Lilly), recombinant insulin lispro (Humalog®; Lilly), recombinant insulin aspart (NovoRapid® Penfill®; Novo Nordisk), recombinant insulin detemir (Levemir®; Novo Nordisk) and recombinant insulin glargine (Lantus®; Sanofi-Aventis) were analyzed. The impurities of insulin analogs were isolated by RP-HPLC and identified with peptide mass fingerprinting using MALDI-TOF/TOF mass spectrometry. The identified derivatives were N-terminally truncated insulin analog impurities of decreased molecular mass of 119, 147 and 377 Da related to the original protein. The modifications resulting in a mass decrease were detected at the N-terminus of B chains of insulin lispro, insulin aspart, human insulin, insulin glargine, insulin detemir in all tested formulations. To our knowledge it is the first time that these impurities are reported. The following derivatives formed by truncation of the B chain in insulin analogs were identified in pharmaceutical formulations: desPhe B1 -N-formyl-Val B2 derivative, desPhe B1 derivative, pyroGlu B4 derivative.

Characteristics and Medication Use of Psoriasis Patients Who May or May Not Qualify for Randomized Controlled Trials.

PubMed

Malatestinic, William; Nordstrom, Beth; Wu, Jashin J; Goldblum, Orin; Solotkin, Kathleen; Lin, Chen-Yen; Kistler, Kristin; Fraeman, Kathy; Johnston, Joseph; Hawley, Lcdr Lesley; Sicignano, Nicholas; Araujo, Andre

2017-03-01

Clinical trials impose exclusion criteria that may limit the generalizability of results. To (a) determine the percentage of real-world patients who would qualify for psoriasis randomized controlled trials; (b) ascertain differences between moderate-to-severe psoriasis patients who would be eligible, ineligible, or potentially eligible for clinical trials; and (c) compare their biologic treatment patterns. Moderate-to-severe psoriasis patients were identified from the U.S. Department of Defense health care database from January 1, 2008, to October 31, 2013. Eligibility classification for psoriasis trials was based on common trial exclusion criteria involving medical conditions and recent treatment history. Patient characteristics and treatment patterns of 4 biologics (adalimumab, etanercept, infliximab, and ustekinumab) were compared between groups. Adherence was measured by medication possession ratio and persistence as continuous time on drug with ≤ 90-day gap between supply times. Among 16,284 qualifying psoriasis patients, 4,677 (28.7%) were medically ineligible, and 8,466 (52.0%) had ineligibility-related treatments that could be stopped prior to trial entry; the latter patients were considered potentially eligible for psoriasis trials. Common reasons for medical ineligibility included malignancies and hematologic disorders; treatment ineligibilities included use of topical corticosteroids and phototherapy. Medically ineligible patients were older and had more comorbidities, while potentially eligible patients were younger and healthier than trial-eligible patients. Most treatment patterns were similar across groups, except that, compared with the trial-eligible group, medically ineligible patients had greater adherence to infliximab and potentially trial-eligible patients had greater adherence and persistence to adalimumab. This large real-world study found that patients who may be ineligible for psoriasis trials differ in important respects (e.g., comorbidities, prior treatments) from their trial-eligible counterparts. Regardless of their differences at baseline, adherence, persistence, and switching of biologic medications are largely similar, with few differences noted among groups. Financial support for this study was provided by Lilly USA. Wu has received research funding from AbbVie, Amgen, AstraZeneca, Boehringer Ingelheim, Coherus Biosciences, Dermira, Eli Lilly, Janssen, Merck, Novartis, Pfizer, Regeneron, Sandoz, and Sun Pharmaceutical Industries, and he is a consultant for AbbVie, Amgen, Celgene, Dermira, Eli Lilly, Pfizer, Regeneron, and Sun Pharmaceutical Industries. Malatestinic, Goldblum, Solotkin, Lin, Johnston, and Araujo are employees and/or stock owners of Lilly. Nordstrom, Kistler, and Fraeman are employees of Evidera, which received funding from Lilly to conduct this study. LCDR Hawley is a military service member. This work was prepared as part of her official duties. Title 17 U.S.C. 105 provides that "copyright protection under this title is not available for any work of the United States Government." Title 17 U.S.C. 101 defines a U.S. government work as a work prepared by a military service member or employee of the U.S. government as part of that person's official duties. Research data were derived from an approved Naval Medical Center, Portsmouth, Virginia, institutional review board protocol. The views expressed in this work are those of the authors and do not necessarily reflect the official policy or position of the Department of the Navy, Department of Defense, or the U.S. government. Study concept and design were contributed by Malatestinic and Araujo, along with the other authors. Nordstrom, Kistler, Fraeman, and Sicignano collected the data, and data interpretation was performed by Wu, Lin, and Hawley, along with Malatestinic, Nordstrom, Solotkin, and Araujo. The manuscript was written by Johnston, Malatestinic, Kistler, Wu, and Araujo, along with Nordstrom, Goldblum, Solotkin, Hawley, and Sicignano, and revised by Goldblum, Solotkin, Malatestinic, and Araujo, along with Nordstrom, Wu, Fraeman, Johnston, Hawley, and Sicignano.

Theoretical and Experimental Study of Vortex Tubes

DTIC Science & Technology

1950-06-01

i ^;’^j©^t^""#=-v"’’ --&••&> -®^il^--«-ö? luv i s-.- 4i -.-«äS ,. -^U£^M09inHnft^tf<ii> iWtBtggF~«>tte*rT&ttTaf-~?* Ä=*»-.Ä*- • MM’ *a...sSet3)&&SSSBS£*lBä28ttSill • i «c .;-,.’. $fo» » -5 *$*?* i ->! .3! °.S, •ii 𔃻.’ * -. i A’ - ’ -~^^ ..# ’$* ;--•.».’ s la...34 -:b • :WS? ’ ’t,T? r;£ I ’.—J’L^A^fc- v/,: LUSTS > S^-’Vt,",; •t

Cell Penetrating Bispecific Antibodies for Targeting Oncogenic Transcription Factors in Advanced Prostate Cancer

DTIC Science & Technology

2016-12-01

biochemical and biologic assay systems. The final specific aim was tol examine the ability of the bispecific antibody to perturb the growth of prostate ...designated by other documentation. TITLE: Cell-Penetrating Bispecific Antibodies for Targeting Oncogenic Transcription Factors in Advanced Prostate ...Bispecific Antibodies for Targeting Oncogenic Transcription Factors in Advanced Prostate Cancer Michael Lilly, MD Richard Weisbart, MD Medical

Saint Mary's College Teacher Science Institute: Converting Teachers to Using Guided Inquiry for Science Curricula

ERIC Educational Resources Information Center

McCarthy, Deborah; Bellina, Joseph J., Jr.

2003-01-01

In 1988 Saint Mary's College received a grant from Lilly Endowment, Inc. to create a program to improve the quality of science education in the local public and private schools. As part of applying that grant we created one-week summer work-shops for elementary and middle school teachers (K-8) based on guided inquiry methods of education. Each…

Context and Domain Knowledge Enhanced Entity Spotting in Informal Text

NASA Astrophysics Data System (ADS)

Gruhl, Daniel; Nagarajan, Meena; Pieper, Jan; Robson, Christine; Sheth, Amit

This paper explores the application of restricted relationship graphs (RDF) and statistical NLP techniques to improve named entity annotation in challenging Informal English domains. We validate our approach using on-line forums discussing popular music. Named entity annotation is particularly difficult in this domain because it is characterized by a large number of ambiguous entities, such as the Madonna album "Music" or Lilly Allen's pop hit "Smile".

Biotechnology Symposium

DTIC Science & Technology

1990-10-01

entire phylum of animals, the Echinodermata (seastars, sea urchins , sea cucumbers, sea lillies, and brittle stars), the voluntary control of mechanical...these materials can vary from stretchy to rigid, they are called catch connective tissues [10]. At the base of each rigid calcitic spine of a sea urchin ...ligament of sea urchins there is a ganglion (cluster of nerve cells) attached to each ligament. Axons extend from nerve cell bodies in the ganglion 898

Toxic Hazards Research Unit Annual Technical Report: 1984

DTIC Science & Technology

1984-09-01

exposed to TOCP exhibited the classic lesions of delayed neuropathy (Smith and Lillie, 1931; Barnes and Denz, 1953; (avanagh, 1954; and Fenton , 1955...Safety of *.i Chemicals in Food, Drugs, and Cosmetics , The staff of the Divi- sion of Pharmacology of the Federal Food and Drug Administration, Austin...Annual Technical Report: 1967, AMRL-TR-67-137 (AD 834723), Aerospace Medical Research Laboratory, Wright-Patterson Air Force Base, Ohio. Fenton , J. C

The Kubo-Greenwood expression and 2d MIT transport

NASA Astrophysics Data System (ADS)

Castner, Theodore

2010-03-01

The 2d MIT in GaAs heterostructures (p- and n-type)features a mobility that drops continuously as the reduced density x= n/nc-1 is decreased. The Kubo-Greenwood result [1] predicts μ = (eɛh/hnc)α^2(x) where α is a normalized DOS. α(x)is obtained from the data [p-type, Gao et al. [2]; n-type Lilly et al. [3

Two protogalaxy candidates in one night

NASA Technical Reports Server (NTRS)

Eisenhardt, Peter; Dickinson, Mark

1993-01-01

In spite of a lookback time of 77 to 89 percent of the age of the universe, Lilly provided evidence that the dominant stellar population in 0902 was surprisingly old, over 1 Gyr. This age estimate was based on the values K = 18.8 and I-K = 4.5 in the central 3.5 x 3.5 inch. At Lilly's suggestion, we reobserved 0902 at K, and in initial reductions of our data found only an upper limit (K greater than 19.5). After extensive experimentation with reduction techniques and correction for low-level systematic effects, we succeeded in extracting a four sigma detection at K = 19.9 in a 4 inch diameter circular aperture. The morphology and location of this detection were more reminescent of the Ly alpha image than of CCD continuum images, and in Mar. 1992, we obtained a narrow band image which included redshifted (OIII) 4959,5007 A line emission at 2.20 microns. This (OIII) image gave a strong detection which demonstrates that most of the central K flux, already reduced by a magnitude, is due to line emission. Our formal line corrected values in a 4 inch aperture are K = 21.5 and R-K = 1.9. Hence, 0902 has been transformed from relaxed maturity into unsettled youth.

Experimental and LES investigation of premixed methane/air flame propagating in a tube with a thin obstacle

NASA Astrophysics Data System (ADS)

Chen, Peng; Guo, Shilong; Li, Yanchao; Zhang, Yutao

2017-03-01

In this paper, an experimental and numerical investigation of premixed methane/air flame dynamics in a closed combustion vessel with a thin obstacle is described. In the experiment, high-speed video photography and a pressure transducer are used to study the flame shape changes and pressure dynamics. In the numerical simulation, four sub-grid scale viscosity models and three sub-grid scale combustion models are evaluated for their individual prediction compared with the experimental data. High-speed photographs show that the flame propagation process can be divided into five stages: spherical flame, finger-shaped flame, jet flame, mushroom-shaped flame and bidirectional propagation flame. Compared with the other sub-grid scale viscosity models and sub-grid scale combustion models, the dynamic Smagorinsky-Lilly model and the power-law flame wrinkling model are better able to predict the flame behaviour, respectively. Thus, coupling the dynamic Smagorinsky-Lilly model and the power-law flame wrinkling model, the numerical results demonstrate that flame shape change is a purely hydrodynamic phenomenon, and the mushroom-shaped flame and bidirectional propagation flame are the result of flame-vortex interaction. In addition, the transition from "corrugated flamelets" to "thin reaction zones" is observed in the simulation.

Open innovation for phenotypic drug discovery: The PD2 assay panel.

PubMed

Lee, Jonathan A; Chu, Shaoyou; Willard, Francis S; Cox, Karen L; Sells Galvin, Rachelle J; Peery, Robert B; Oliver, Sarah E; Oler, Jennifer; Meredith, Tamika D; Heidler, Steven A; Gough, Wendy H; Husain, Saba; Palkowitz, Alan D; Moxham, Christopher M

2011-07-01

Phenotypic lead generation strategies seek to identify compounds that modulate complex, physiologically relevant systems, an approach that is complementary to traditional, target-directed strategies. Unlike gene-specific assays, phenotypic assays interrogate multiple molecular targets and signaling pathways in a target "agnostic" fashion, which may reveal novel functions for well-studied proteins and discover new pathways of therapeutic value. Significantly, existing compound libraries may not have sufficient chemical diversity to fully leverage a phenotypic strategy. To address this issue, Eli Lilly and Company launched the Phenotypic Drug Discovery Initiative (PD(2)), a model of open innovation whereby external research groups can submit compounds for testing in a panel of Lilly phenotypic assays. This communication describes the statistical validation, operations, and initial screening results from the first PD(2) assay panel. Analysis of PD(2) submissions indicates that chemical diversity from open source collaborations complements internal sources. Screening results for the first 4691 compounds submitted to PD(2) have confirmed hit rates from 1.6% to 10%, with the majority of active compounds exhibiting acceptable potency and selectivity. Phenotypic lead generation strategies, in conjunction with novel chemical diversity obtained via open-source initiatives such as PD(2), may provide a means to identify compounds that modulate biology by novel mechanisms and expand the innovation potential of drug discovery.

Readability Formulas and Air Force Publications: A Review of Their Development and an Examination of Their Application.

DTIC Science & Technology

1989-09-01

Us e o f t he Autf o mat ( d R, ~hI- I f I nd ex -to A\\-S ( ss- C ompreon iL Iit f Nir UreT-chniiil1Orders, November 1967. Tech -nical R( -1 SEG-TP...MEN or THEIR EUELO (U) AIR FORM lust Or TECH WRIGHT-PATTERSON 4WD ON SCHOOL OF SYST..UNCASSIFIED T FEMKINHOF SEP 09 OWITI L/LSR/89S-22 F/O 5/2 HL...their timely assistance in my search for obtaining the various arti-zle- used in this research. I am also deeply indt-bted to rry advisor, Dr. David K

Love, Lust, and Loss in the Early Age of AIDS: The Discourse in the Body Politic From 1981 to 1987.

PubMed

McKenzie, Cameron

2016-12-01

This article explores the idea that the AIDS epidemic constituted a defining moment for the Canadian gay rights movement and illuminates the intricate power dynamics of the development of a community identity. Using grounded theory inductive and deductive content analysis, and interviews with activists from the Body Politic magazine, this article considers notions of health "from above" and "from below" by examining relations between the community and government and their confrontation with medicalization and the medical profession. I also examine how the magazine reported and negotiated issues related to the community's self-policing and "self-managed oppression" through efforts to promote safer sex and risk reduction.

Prevention and Management of Infections Associated With Burns in the Combat Casualty

DTIC Science & Technology

2008-03-01

even including staff members, to detect “carriers” of such organisms as methicillin - resistant S. aureus (MRSA) and drug- resistant gram-negatives.80–83...Lilly HA, Lowbury EJ. Antibiotic resistance of Staphylococcus aureus in a burns unit after stopping routine prophylaxis with erythromycin. J...nosocomial transmission of multidrug- resistant strains of Staphylococcus aureus and Enterococcus. Infect Control Hosp Epi. 2003;24:362–386. 89. Siegel JD

Command History, 1993.

DTIC Science & Technology

1994-04-01

that the peripheral vasoconstriction resulting from cold exposure leads to an increase in central venous return, increased central venous pressure, and...AD-A279 775 -; lilli IIIIIII lIII 11lU~lMuli/II I IIIll 1993 COMMAND HISTORY Compiled by R. E. Gadolin and K. S. Mayer DTIC SL ELECTE MAYSI11941) v F...distribution unlimited. NAVAL AEROSPACE MEDICAL RESEARCH LABORATORY 51 HOVEY ROAD, PENSACOLA, FLORIDA 32508-1046 1993 COMMAND HISTORY Compiled by R.E. Gadolin

The Design and Implementation of a Data Flow Multiprocessor.

DTIC Science & Technology

1981-12-01

to thank Captain Charles Papp who taught me how to use the logic analyzer and the storage oscilloscope. Without these tools, I could never have...debugged and repaired the microprocessors. Finally, I wish to thank my thesis readers, Major Charles Lillie and Major Walt Seward, for taking valuable time...Neumann/ Babbage architecture with the a data flow architecture. The next section describes the benefits of data flow computing. The following section

Governing for Enterprise Security (GES) Implementation Guide

DTIC Science & Technology

2007-08-01

Lilly for its inadvertent failure to uphold a pri- vacy promise it had made to patients using Prozac , even though it had a policy covering the op...FITNESS FOR PURPOSE OR MERCHANTABILITY, EXCLUSIVITY, OR RESULTS OBTAINED FROM USE OF THE MATERIAL. CARNEGIE MELLON UNIVERSITY DOES NOT MAKE ANY WARRANTY...OF ANY KIND WITH RESPECT TO FREEDOM FROM PATENT, TRADEMARK, OR COPYRIGHT INFRINGEMENT. Use of any trademarks in this report is not intended in any

Patient Characteristics, Health Care Resource Utilization, and Costs Associated with Treatment-Regimen Failure with Biologics in the Treatment of Psoriasis.

PubMed

Foster, Shonda A; Zhu, Baojin; Guo, Jiaying; Nikai, Enkeleida; Ojeh, Clement; Malatestinic, William; Goldblum, Orin; Kornberg, Lori J; Wu, Jashin J

2016-04-01

Psoriasis is a chronic, incurable, and immune-mediated skin disorder that is characterized by erythematous scaly papules and plaques. Understanding of psoriasis at the molecular level has led to the development of biologic agents that target disease-specific inflammatory mediators in psoriatic lesions. Biologic agents have become important components of the psoriasis armamentarium, but some patients become refractory to these agents over time or fail to respond to subsequent biologics. To (a) evaluate demographic and clinical characteristics of psoriasis patients who have treatment patterns suggestive of failure to a newly initiated biologic agent (treatment-regimen failures) compared with those who do not (non-treatment-regimen failures) and (b) to assess health care-related resource utilization and costs in non-treatment-regimen failures and treatment-regimen failures. In this retrospective observational cohort study, patients were selected from the MarketScan claims database of commercially insured individuals and individuals with Medicare supplemental insurance. The index event was a newly initiated biologic agent for the treatment of psoriasis (etanercept, adalimumab, ustekinumab, or infliximab) between January 2010 and December 2011. The analysis included psoriasis patients aged ≥ 18 years with ≥ 1 prescription claim for a biologic and continuous enrollment 12 months pre- and post-index date. Patients with claims for a biologic in the pre-index period were excluded. Patients were divided into treatment-regimen-failure and non-treatment-regimen-failure groups based on their treatment patterns post-index date. The treatment-regimen-failure group included patients who switched to another biologic, discontinued the biologic without restarting, increased the dose of the biologic, or augmented treatment with a nontopical psoriasis medication during the post-index period. Between-group patient characteristics and medication use were compared using analysis of variance for continuous variables and chi-square tests for categorical variables without adjustment. Cost differences were compared using the propensity score-adjusted bin bootstrapping method. Overall, 2,146 patients met the enrollment criteria. The mean age was 45.1 years. Of these patients, 41.5% were considered treatment-regimen failures. Among treatment-regimen failures, 53% were females, and among non-treatment-regimen failures, 61% were male. Patients who experienced treatment-regimen failure had higher incidences of comorbid cerebrovascular disease, hypertension, chronic pulmonary disease, depression, and anxiety in the pre-index period and were more likely to use concomitant topicals (67.0% vs. 58.4%; P < 0.001), methotrexate (20.2% vs. 7.3%; P < 0.001), and cyclosporine (3.1% vs. 1.0%; P < 0.001) in the post-index period. Mean total all-cause health care costs were higher in patients with treatment-regimen failure versus non-treatment-regimen failure during the pre-index period ($8,024 vs. $6,637; P = 0.002), but patients with non-treatment-regimen failure had higher all-cause costs ($30,759 vs. $28,012; P = 0.002) and psoriasis-related costs ($25,286 vs. $19,625; P < 0.001) during the post-index period. The results of the current study demonstrated that psoriasis patients with treatment patterns suggestive of treatment-regimen failure on an index biologic had different characteristics and incurred higher all-cause health care costs than did patients without treatment-regimen failure during the pre-index period. This study was supported by Eli Lilly and Company. Foster, Zhu, Guo, Nikai, Malatestinic, Ojeh, and Goldblum are full-time employees and stockholders of Eli Lilly and Company. Kornberg is a full-time employee of INC Research, which was contracted by Eli Lilly to assist with medical writing. Wu has received research funding from AbbVie, Amgen, Coherus Biosciences, Eli Lilly, Janssen, Merck, Novartis, Pfizer, Regeneron, and Sandoz; he is a consultant for AbbVie, Amgen, Celgene, Dermira, DUSA Pharmaceuticals, Eli Lilly, and Pfizer. Study concept was developed by Foster, Ojeh, Malatestinic, and Goldblum. Zhu and Guo, along with Foster, took the lead in data collection, and data interpretation was performed by Nikai, Wu, and Foster, with assistance from the other authors. The manuscript was primarily written by Kornberg, along with Foster, with assistance from the other authors. All of the authors were involved with manuscript revision.

Evaluation and Validation (E&V) Team Public Report. Volume 2.

DTIC Science & Technology

1985-11-30

Byron, Countess of Lovelace. The Countess was an associate of Charles Babbage and is presumed to be the world’s first programmer (Barnes, 1982:2...by DDT&E, STARS, and AJPO personnel, as appropriate. 4.20.9 Focal Point The DDT&E and STARS focal points, respectively, are indicated below Charles K...Technology For Adaptable, Reliable Systems Major Charles W. Lillie from Headquarters Air Force Systems Command gave a presentation concerning Software For

Super Hydrides.

DTIC Science & Technology

1988-03-01

enantioselective synthesis Of the clinically important anti-depressants, (-)Tomoxetine, Fluoxetine (Prozac, Eli Lilly), and Nisoxetine (Scheme 1 ). Schem I a I...Scheme 1 . Another salient feature of this synthesis is that it correlated for the first time the absolute configuration of the enantiomers of...RD-RI93 710 SUPER HYDRIDES(U) PURDUE UNIV LRFRYETTE IN H C BROWN 1 / 1 NAR 88 RRO-22302.2-CN DAR29-05-K-1662 UNCLSSIFIED F/G 7/3 NI. t2S 16, L,. 10 3

[Rapid method of silver nitrate impregnation of elements of the peripheral nervous system suitable for celloidin and paraffin sections].

PubMed

Kolomiĭtsev, A K; Chaikovskiĭ, Iu B; Tereshchenko, T L

1981-08-01

According to the method of neural elements impregnation in the authors' modification, the object is fixed for 6-12 h in Lillie fluid cooled to 4 degrees C. Then the object is kept under tap water for 2-6 h. Frozen sections are prepared and kept in pure pyridine for 1-6 h. When the sections are embedded into paraffin or celloidin, they are put into alcohol solutions gradually decreasing their concentration until water is reached, then put into pyridine. In order to remove cellulose, the celloidin sections are treated in 3 portions of pyridine (in the 1st and 2nd-for 10 min, and in the 3d-for 6 h). Then they are washed under tap water for 2-4 h and in distilled water for 30-40 min. Further treatment is performed according to the methods by Bielschowsky - Gros, Kampos or Rasskazova. Excess silver is removed by treating the sections in 2% ammonium persulfate under the microscope control (the process is stopped by putting the sections into 7% sodium hyposulfate for 10 min). Then the sections are treated in 0.1% aurum chloride, in 5% hyposulfite to reveale the tissue background [corrected] and by means of routine histological techniques either after Brashet, Hale, PAS-positive reaction or other methods applied after fixation in Lillie fluid.

KSC00spn002

NASA Image and Video Library

2001-07-26

KENNEDY SPACE CENTER, FLA. -- Day in the Life page 2. Preparing the pad. Workers maintain Pad A at Kennedy Space Center’s Launch Complex 39. Robert Lust of IVEY Construction pauses on his way to install a safety handrail. This photograph was taken for a special color edition of Spaceport News designed to portray in photographs a single day at KSC, July 26, 2000. The special edition, published Aug. 25, 2000, was created to give readers a look at KSC’s diverse workforce and the critical roles workers play in the nation’s space program. Spaceport News is an official publication of the Kennedy Space Center and is published on alternate Fridays by the Public Affairs Office in the interest of KSC civil service and contractor employees

Resolution of Low Back and Radicular Pain in a 40-year-old Male United States Navy Petty Officer after Collaborative Medical and Chiropractic Care

DTIC Science & Technology

2009-12-08

www.journalchiromed.com Journal of Chiropractic Medicine (2010) 9, 17–21Resolution of low back and radicular pain in a 40-year-old male United States...Navy Petty Officer after collaborative medical and chiropractic care☆ Gregory R. Lillie DC, MS⁎ Chiropractic Physician, Naval Branch Health Clinic...Military personnel; ChiropracticObjective: The aim of this study is to describe the interdisciplinary care, including chiropractic services, in a military

Effect of Moderate Hypothermia on Gene Expression by THP-1 Cells: A DNA Microarray Study

DTIC Science & Technology

2006-01-01

h was found to improve both survival and neurological outcomes in newborn infants suffering from hypoxic-ischemic encephalopathy (17). Al- though the...from adults and newborns . J Interferon Cytokine Res 20: 1049–1055, 2000. 7. Farrell RE Jr. Determination of nucleic acid concentration and purity. In...hypoxic-ischemic encephalopathy . N Engl J Med 353: 1574–1584, 2005. 18. Sonna LA, Cullivan ML, Sheldon HK, Pratt RE, and Lilly CM. Effect of hypoxia

A Long Term Assessment of the Clinical Efficacy of the Fiberotomy as it Relates to Rotational Relapse.

DTIC Science & Technology

1983-01-01

physical. The physical function held the tooth in place, resisted displacement, and "supported the soft tissues about the teeth." He believed that...and the tissues fixed. Separations of 0.75 to 2.0 mm were obtained. Histologic examination revealed tearing of the periodontal fibers on the tension...alveolar fibers which terminate in soft tissues revealed the same degree of tearing. In 1958, Fullmer and Lillie discovered a previously unobserved

Drotrecogin alfa (activated)...a sad final fizzle to a roller-coaster party.

PubMed

Angus, Derek C

2012-02-06

Following the failure of PROWESS-SHOCK to demonstrate efficacy, Eli Lilly and Company withdrew drotrecogin alfa (activated) from the worldwide market. Drotrecogin was initially approved after the original trial, PROWESS, was stopped early for overwhelming efficacy. These events prompt consideration of both the initial approval decision and the later decision to withdraw. It is regrettable that the initial decision was made largely on a single trial that was stopped early. However, the decision to approve was within the bounds of normal regulatory practice and was made by many approval bodies around the world. Furthermore, the overall withdrawal rate of approved drugs remains very low. The decision to withdraw was a voluntary decision by Eli Lilly and Company and likely reflected key business considerations. Drotrecogin does have important biologic effects, and it is probable that we do not know how best to select patients who would benefit. Overall, there may still be a small advantage to drotrecogin alfa, even used non-selectively, but the costs of determining such an effect with adequate certainty are likely prohibitive, and the point is now moot. In the future, we should consider ways to make clinical trials easier and quicker so that more information can be available in a timely manner when considering regulatory approval. At the same time, more sophisticated selection of patients seems key if we are to most wisely test agents designed to manipulate the septic host response.

Root cause investigation of a viral contamination incident occurred during master cell bank (MCB) testing and characterization--a case study.

PubMed

Chen, Dayue; Nims, Raymond; Dusing, Sandra; Miller, Pamela; Luo, Wen; Quertinmont, Michelle; Parekh, Bhavin; Poorbaugh, Josh; Boose, Jeri Ann; Atkinson, E Morrey

2008-11-01

An adventitious agent contamination occurred during a routine 9 CFR bovine viral screening test at BioReliance for an Eli Lilly Chinese Hamster Ovary (CHO) cell-derived Master Cell Bank (MCB) intended for biological production. Scientists from the sponsor (Eli Lilly and Company) and the testing service company (BioReliance) jointly conducted a systematic investigation in an attempt to determine the root cause of the contamination. Our investigation resulted in the identification of the viral nature of the contaminant. Subsequent experiments indicated that the viral contaminant was a non-enveloped and non-hemadsorbing virus. Transmission electron microscopy (TEM) revealed that the viral contaminant was 25-30 nm in size and morphologically resembled viruses of the family Picornaviridae. The contaminant virus was readily inactivated when exposed to acidic pH, suggesting that the viral contaminant was a member of rhinoviruses. Although incapable of infecting CHO cells, the viral contaminant replicated efficiently in Vero cell with a life cycle of approximately 16 h. Our investigation provided compelling data demonstrating that the viral contaminant did not originate from the MCB. Instead, it was introduced into the process during cell passaging and a possible entry point was proposed. We identified the viral contaminant as an equine rhinitis A virus using molecular cloning and DNA sequencing. Finally, our investigation led us to conclude that the source of the viral contaminant was the equine serum added to the cell growth medium in the 9 CFR bovine virus test.

The riddle of sex: biological theories of sexual difference in the early twentieth-century.

PubMed

Ha, Nathan Q

2011-01-01

At the turn of the twentieth century, biologists such as Oscar Riddle, Thomas Hunt Morgan, Frank Lillie, and Richard Goldschmidt all puzzled over the question of sexual difference, the distinction between male and female. They all offered competing explanations for the biological cause of this difference, and engaged in a fierce debate over the primacy of their respective theories. Riddle propounded a metabolic theory of sex dating from the late-nineteenth century suggesting that metabolism lay at the heart of sexual difference. Thomas Hunt Morgan insisted on the priority of chromosomes, Frank Lillie emphasized the importance of hormones, while Richard Goldschmidt supported a mixed model involving both chromosomes and hormones. In this paper, I will illustrate how the older metabolic theory of sex was displaced when those who argued for the relatively newer theories of chromosomes and hormones gradually formed an alliance that accommodated each other and excluded the metabolic theory of sex. By doing so, proponents of chromosomes and hormones established their authority over the question of sexual difference as they laid the foundations for the new disciplines of genetics and endocrinology. Their debate raised urgent questions about what constituted sexual difference, and how scientists envisioned the plasticity and controllability of this difference. These theories also had immediate political and cultural consequences at the turn of the twentieth century, especially for the eugenic and feminist movements, both of which were heavily invested in knowledge of sex and its determination, ascertainment, and command.

Neurotic love letters.

PubMed

Tierra, Tatiana De La

2004-01-01

Abstract The intensity of falling in love is expressed through sexual longing and is focused on pleasures of the body. Fresh fruits and vegetables and other elements of nature-wind, birds, foliage-form part of the setting of seduction. Being in love with another woman makes the entire world beautiful. But the lesbian paradise is eventually eclipsed by bitter realities that intrude upon the relationship-the ever-present ex-lover (still in the picture), family ties (with homophobic overtones), business connections (that imperil lesbian economic independence), and issues of commitment and honesty that eventually lead to betrayal and a bittersweet breakup. Based on correspondence originally written in Spanish, "Neurotic Love Letters" is a testament to an unfortunate fact-that all the love and lust between two women cannot always conquer dubious circumstances and harsh realities unique to lesbian relationships.

The medicalization of love.

PubMed

Earp, Brian D; Sandberg, Anders; Savulescu, Julian

2015-07-01

Pharmaceuticals or other emerging technologies could be used to enhance (or diminish) feelings of lust, attraction, and attachment in adult romantic partnerships. Although such interventions could conceivably be used to promote individual (and couple) well-being, their widespread development and/or adoption might lead to the 'medicalization' of human love and heartache--for some, a source of a serious concern. In this essay, we argue that the medicalization of love need not necessarily be problematic, on balance, but could plausibly be expected to have either good or bad consequences depending upon how it unfolds. By anticipating some of the specific ways in which these technologies could yield unwanted outcomes, bioethicists and others can help to direct the course of love's medicalization--should it happen to occur--more toward the 'good' side than the 'bad.'

Engineering study comparing injection force and dose accuracy between two prefilled insulin injection pens.

PubMed

Ignaut, Debra A; Opincar, Michael R; Clark, Paula E; Palaisa, Melanie K; Lenox, Sheila M

2009-12-01

This study compared injection force (measured by glide force [GF] and glide force variability [GFV]) and dosing accuracy of the Humalog KwikPen * (prefilled insulin lispro [Humalog dagger] pen, Eli Lilly and Company, Indianapolis, IN) and the Next Generation FlexPen double dagger (prefilled insulin aspart [NovoRapid section sign] pen, Novo Nordisk A/S, Bagsvaerd, Denmark). * Humalog KwikPen is a registered trademark of Eli Lilly and Company, Indianapolis, IN, USA. dagger Humalog is a registered trademark of Eli Lilly and Company, Indianapolis, IN, USA. double dagger FlexPen is a registered trademark of Novo Nordisk A/S, Bagsvaerd, Denmark. section sign NovoRapid is a registered trademark of Novo Nordisk A/S, Bagsvaerd, Denmark. A total of 100 prefilled insulin pens (50 insulin lispro pens, 50 insulin aspart pens) were tested using two dose sizes (30 U and 60 U). In all, 50 devices (25 of each type) were tested at 10 U/s dosing speed and 50 were tested at 6.6 U/s. Devices were used per manufacturer instructions. Dose accuracy (represented as absolute dose error %), maximum and average GF, and GFV data were automatically collected by the test system for all datasets (dose size/dosing speed/device type). The test system controlled for potential dosing errors. The insulin lispro pen demonstrated a significantly lower median maximum GF at both dosing speeds: (2.83 vs. 3.92 lbs [30 U] and 3.00 vs. 4.14 lbs [60 U]) at 10 U/s; (1.85 vs. 2.93 lbs [30 U] and 2.14 vs. 3.02 lbs [60 U]) at 6.6 U/s, all p < 0.0001. For all datasets, the median GFV was significantly lower for the insulin lispro pen, p < 0.0001. Median dose error was comparable between device types when tested at 10 U/s dosing speed; however, at 6.6 U/s, the median dose error was significantly lower for insulin lispro pen compared to insulin aspart pen (0.47 vs. 0.67% [30 U] and 0.50 vs. 0.78% [60 U], both p < 0.05). The insulin lispro pen had significantly lower median GF and GFV compared with insulin aspart pen when tested at two dose sizes and two dosing speeds. Median dose error was similar between the device types at the 10 U/s dosing speed, but median dose error was significantly lower for the insulin lispro pen at the 6.6 U/s dosing speed. A limitation of this study was that it was executed as an open label study.

The Subchronic Inhalation Toxicity of DF2 (Diesel Fuel) Used in Vehicle Engine Exhaust Smoke Systems (VEESS).

DTIC Science & Technology

1986-03-01

4-I +4 .- -+ + _C tL+ + + +i + T + +- + - -) 4. c_ --- - * - 4A _ __ _ -- 0 0 ICx" C ) 4j cliou 0 N4cr(\\lc’ + + ++ ++ + + +1 -4++111+ = 0 m x...Charles L. Crouse SP6 David C . Burnett Garnet E. Affleck Dale H. Heitkamp Edmund G. Cummings, Ph.D. Carlyle Lilly Richard L. Farrand, Ph.D. Joseph J...Feeney, Ph.D. Robert W. Dorsey Michael Rausa SP6 Mohammed S. Ghumman Ernest H. Kandel Robert D. Armstrong Jeffrey D. Bergmann William C . Stark. John

The Seventh Data Release of the Sloan Digital Sky Survey

DTIC Science & Technology

2009-05-18

Gilmore17, Belinda Gonzalez2, Carlos F. Gonzalez2, Eva K . Grebel43, James E. Gunn11, Zsuzsanna Györy29, Patrick B . Hall44, Paul Harding45...131, 2332 Gustafsson, B ., Edvardsson, B ., Eriksson, K ., Jørgensen, U. G., Nordlund, Å., & Plez, B . 2008, A&A, 486, 951 Holtzman, J. A., et al. 2008, AJ...Shara, M. M. 2007, ApJ, 669, 1235 Lilly, S., et al. 2007, ApJS, 172, 70 Lisker, T., Grebel, E. K ., Binggeli, B ., & Glatt, K . 2007, ApJ, 660, 1186

Complete NACA Muroc Staff of 1947, in front of the XS-1 and B-29

NASA Technical Reports Server (NTRS)

1947-01-01

The NACA Muroc Contingent in October 1947 in front of the Bell Aircraft Corporation X-1-2 and Boeing B-29 launch aircraft. Standing left to right: Le Roy Proctor, Jr., Don Borchers, Harold Nemecek, Phyllis Actis Rogers, Milton McLaughlin, Roxanah Yancey, Arthur 'Bill' Vernon, Dorothy Clift Hughes, Naomi C. Wimmer, Frank Hughes, John Mayer, Elmer Bigg, De E. Beeler. Kneeling left to right: Charles Hamilton, Joseph Vensel, Herbert Hoover, Hubert Drake, Eugene Beckwith, Walter Williams, Harold Goodman, Howard Lilly, John Gardner.

New application system for laser and ultrasonic therapy in endoscopic surgery

NASA Astrophysics Data System (ADS)

Desinger, Kai; Helfmann, Juergen; Stein, Thomas; Mueller, Gerhard J.

1996-12-01

Flexible acoustic waveguides for selective tissue fragmentation are not yet commercially available. Experimental studies have shown the possibility of transmission of acoustical transients via optical silica glass fibers. The aim of this project is the development of a new endoscopic application system that would enable surgeons to use the laser and the ultrasound technique for therapy simultaneously. The concept of this application system is based on the transmission of laser radiation and ultrasound power via flexible silica glass fibers. Theoretical and experimental results on the feasibility of such an application system for an ultrasonic power delivery system are presented. Piezo-electric transducers are used to provide a high efficiency in generating the ultrasonic power. With reference to the CUSA-technique, a special flexible guiding system has been designed for providing aspiration at the tip and for protection of the fiber. The system transmits via an optical fiber up to 100 Watt Nd:YAG laser radiation. The axial oscillation of the fiber tip is +/- micrometers at a frequency of 27 kHz. First results of in vitro experiments are presented. The parenchymatous cells of liver can be fragmented without destruction of the collagenous matrix. The laser can be optionally used to coagulate bleedings or to cut collagenous tissues in contact. Applications for an acoustical and optical waveguide in ultrasonic surgery are demonstrated. This new approach in developing a first application system for the therapeutical use of laser radiation and power ultrasound in minimal invasive surgery via optical waveguides offers new possibilities in surgery. The laser ultrasonic surgical therapy (LUST) with its thin and flexible applicator provides new working fields especially for neuro or liver surgery. The tip can be bent and thus areas which could not be treated before have now been made accessible. Without changing the instrumentation, the surgeon can use the laser for tissue coagulation or cutting, next to the selective ultrasonic tissue fragmentation, where nerves or vessels will not be affected. Such a LUST-application system could be ready for clinical use in two to four years.

Eli Lilly and Company's bioethics framework for human biomedical research.

PubMed

Van Campen, Luann E; Therasse, Donald G; Klopfenstein, Mitchell; Levine, Robert J

2015-11-01

Current ethics and good clinical practice guidelines address various aspects of pharmaceutical research and development, but do not comprehensively address the bioethical responsibilities of sponsors. To fill this void, in 2010 Eli Lilly and Company developed and implemented a Bioethics Framework for Human Biomedical Research to guide ethical decisions. (See our companion article that describes how the framework was developed and implemented and provides a critique of its usefulness and limitations.) This paper presents the actual framework that serves as a company resource for employee education and bioethics deliberations. The framework consists of four basic ethical principles and 13 essential elements for ethical human biomedical research and resides within the context of our company's mission, vision and values. For each component of the framework, we provide a high-level overview followed by a detailed description with cross-references to relevant well regarded guidance documents. The principles and guidance described should be familiar to those acquainted with research ethics. Therefore the novelty of the framework lies not in the foundational concepts presented as much as the attempt to specify and compile a sponsor's bioethical responsibilities to multiple stakeholders into one resource. When such a framework is employed, it can serve as a bioethical foundation to inform decisions and actions throughout clinical planning, trial design, study implementation and closeout, as well as to inform company positions on bioethical issues. The framework is, therefore, a useful tool for translating ethical aspirations into action - to help ensure pharmaceutical human biomedical research is conducted in a manner that aligns with consensus ethics principles, as well as a sponsor's core values.

Vicarious revenge and the death of Osama bin Laden.

PubMed

Gollwitzer, Mario; Skitka, Linda J; Wisneski, Daniel; Sjöström, Arne; Liberman, Peter; Nazir, Syed Javed; Bushman, Brad J

2014-05-01

Three hypotheses were derived from research on vicarious revenge and tested in the context of the assassination of Osama bin Laden in 2011. In line with the notion that revenge aims at delivering a message (the "message hypothesis"), Study 1 shows that Americans' vengeful desires in the aftermath of 9/11 predicted a sense of justice achieved after bin Laden's death, and that this effect was mediated by perceptions that his assassination sent a message to the perpetrators to not "mess" with the United States. In line with the "blood lust hypothesis," his assassination also sparked a desire to take further revenge and to continue the "war on terror." Finally, in line with the "intent hypothesis," Study 2 shows that Americans (but not Pakistanis or Germans) considered the fact that bin Laden was killed intentionally more satisfactory than the possibility of bin Laden being killed accidentally (e.g., in an airplane crash).

Priming Sexual and Romantic Representations in Two Media Environments: Sex Encourages and Romance Discourages Sexual Permissiveness … Sometimes.

PubMed

Dillman Carpentier, Francesca R

2017-01-01

Two experiments (Ns = 314, 447) were used to evaluate the effectiveness of sexual cues in temporarily increasing young adults' self-reported sexual permissiveness, as well as the effects of romantic cues in temporarily decreasing permissiveness. Participants were exposed to sexual or romantic cues embedded as a theme-defining component of an online game (Study 1) or in advertisements peripheral to the online game (Study 2). Sexual and romantic conditions were compared against a control condition. As hypothesized, participants in the romantic conditions rated themselves lower in sexual permissiveness, compared to participants in the sexual and control conditions, particularly when participants positively evaluated the online game experience. Findings suggest that exposure to entertaining media depictions of two people, as a committed couple, expressing love, as well as lust, for each other might deter young adults from considering engagement in casual sexual encounters indicative of "hookup culture."

Practical applications of sulfate-reducing bacteria to control acid mine drainage at the Lilly/Orphan Boy Mine near Elliston, Montana

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

Canty, M.

The overall purpose of this document is to provide a detailed technical description of a technology, biological sulfate reduction, which is being demonstrated under the Mine Waste Technology Pilot Program, and provide the technology evaluation process undertaken to select this technology for demonstration. In addition, this document will link the use of the selected technology to an application at a specific site. The purpose of this project is to develop technical information on the ability of biological sulfate reduction to slow the process of acid generation and, thus, improve water quality at a remote mine site. Several technologies are screenedmore » for their potential to treat acid mine water and to function as a source control for a specific acid-generating situation: a mine shaft and associated underground workings flooded with acid mine water and discharging a small flow from a mine opening. The preferred technology is the use of biological sulfate reduction. Sulfate-reducing bacteria are capable of reducing sulfate to sulfide, as well as increasing the pH and alkalinity of water affected by acid generation. Soluble sulfide reacts with the soluble metals in solution to form insoluble metal sulfides. The environment needed for efficient sulfate-reducing bacteria growth decreases acid production by reducing the dissolved oxygen in water and increasing pH. A detailed technical description of the sulfate-reducing bacteria technology, based on an extensive review of the technical literature, is presented. The field demonstration of this technology to be performed at the Lilly/Orphan Boy Mine is also described. Finally, additional in situ applications of biological sulfate reduction are presented.« less

Development, implementation and critique of a bioethics framework for pharmaceutical sponsors of human biomedical research.

PubMed

Van Campen, Luann E; Therasse, Donald G; Klopfenstein, Mitchell; Levine, Robert J

2015-11-01

Pharmaceutical human biomedical research is a multi-dimensional endeavor that requires collaboration among many parties, including those who sponsor, conduct, participate in, or stand to benefit from the research. Human subjects' protections have been promulgated to ensure that the benefits of such research are accomplished with respect for and minimal risk to individual research participants, and with an overall sense of fairness. Although these protections are foundational to clinical research, most ethics guidance primarily highlights the responsibilities of investigators and ethics review boards. Currently, there is no published resource that comprehensively addresses bioethical responsibilities of industry sponsors; including their responsibilities to parties who are not research participants, but are, nevertheless key stakeholders in the endeavor. To fill this void, in 2010 Eli Lilly and Company instituted a Bioethics Framework for Human Biomedical Research. This paper describes how the framework was developed and implemented and provides a critique based on four years of experience. A companion article provides the actual document used by Eli Lilly and Company to guide ethical decisions regarding all phases of human clinical trials. While many of the concepts presented in this framework are not novel, compiling them in a manner that articulates the ethical responsibilities of a sponsor is novel. By utilizing this type of bioethics framework, we have been able to develop bioethics positions on various topics, provide research ethics consultations, and integrate bioethics into the daily operations of our human biomedical research. We hope that by sharing these companion papers we will stimulate discussion within and outside the biopharmaceutical industry for the benefit of the multiple parties involved in pharmaceutical human biomedical research.

Impact of Stainless Steel Exposure on the Oxidation of Polysorbate 80 in Histidine Placebo and Active Monoclonal Antibody Formulation.

PubMed

Gopalrathnam, Ganapathy; Sharma, Anant Navanithan; Dodd, Steven Witt; Huang, Lihua

2018-01-01

Rapid oxidation of polysorbate 80 in histidine buffer was observed upon brief exposure to stainless steel. Liquid chromatography-mass spectrometry analysis indicates degradation of both polyoxyethylene sorbitan and polyoxyethylene head groups and unsaturated fatty acid chains, with further confirmation by reversed-phase high-performance liquid chromatography data. Both Fe 2+ and Fe 3+ were shown to induce polysorbate 80 oxidation. The degree of oxidation in polysorbate 20 and polysorbate 80 are comparable for the head groups and saturated fatty acid esters. However, the same phenomenon was not observed with placebo or monoclonal antibody at a threshold protein concentration, formulated in sodium citrate, in combination with histidine and sodium citrate, or with Na 2 ethylenediaminetetraacetic acid (EDTA). Further, polysorbate 80 oxidation was not observed with Lilly's antibody containing the active ingredient LY2951742, at or above a threshold concentration. Finally, no major polysorbate 80 degradation was observed in histidine buffer, with or without protein, in containers composed of glass or plastic, or when stainless steel exposure was otherwise completely absent. Finally, the 2-oxo oxidation form of histidine was not observed, but the other oxidation products and modifications of histidine were identified. LAY ABSTRACT: Rapid oxidation of polysorbate 80 in histidine buffer was observed upon brief exposure to stainless steel. The degree of oxidation in polysorbate 80 and polysorbate 20 were comparable. However, the same phenomenon was not observed with placebo when formulated in sodium citrate, in combination with histidine and sodium citrate, or with Na 2 ethylenediaminetetraacetic acid (EDTA). Polysorbate 80 oxidation was not observed with Lilly's antibody containing the active ingredient, LY2951742, at or above a threshold concentration. No major polysorbate 80 degradation in histidine buffer was observed when stainless steel contact was completely absent. © PDA, Inc. 2018.

Effect of standard (self-directed) training versus intensive training for Lilly/Alkermes human insulin inhalation powder delivery system on patient-reported outcomes and patient evaluation of the system.

PubMed

Hayes, Risa P; Nakano, Masako; Muchmore, Douglas; Schmitke, Jennifer

2007-02-01

Inhaled insulin may provide patients with diabetes a safe, efficacious method of insulin delivery without the burden of injection, but complexity of and time required for training in proper use of delivery systems have not been evaluated. This 4-week, multicenter, single-blind, randomized parallel-group study compared the effect of self-directed [written text-graphic directions for use (DFU) with patient-assistance phone number] or intensive (same DFU, personal training by study personnel, inspiratory flow rate coaching) training for the Lilly/Alkermes human insulin inhalation powder (HIIP) delivery system on patient-reported outcomes (PROs). Patients with type 2 diabetes poorly controlled on oral therapy (n = 102, mean hemoglobin A1C = 9.3%) were administered measures of vitality, diabetes-associated symptoms, fear of hypoglycemia, insulin-delivery system satisfaction, and a delivery system-specific evaluation questionnaire. Analysis of covariance models were used to compare the effect on PROs of treatment of diabetes for 1 month following the two training methods. Paired t tests were used to determine change in PROs after treatment with HIIP. PROs did not differ significantly between training groups. Patients in both groups positively evaluated the delivery system, but the intensive group agreed significantly (P < 0.05) more strongly that the DFU was easy to follow. Improvements in vitality and symptoms of fatigue and increases in fear of hypoglycemia were detected among all patients after using HIIP (P < 0.05). Training for this HIIP delivery system can be self-directed without detrimental effects on PROs, making it potentially a more patient-friendly insulin-delivery method that should appeal to both clinicians and patients.

Potential Insulin Underdelivery from Prefilled and Reusable Insulin Pens in Cases of Premature Needle Withdrawal: A Laboratory Evaluation.

PubMed

Joubert, Michael; Haddouche, Aini; Morera, Julia; Rod, Anne; Reznik, Yves

2015-10-01

Devices for the treatment of diabetes are not always used as recommended in good practice. Our aim was to evaluate potential insulin underdelivery in cases of premature needle withdrawal after injection with insulin pens, which is a commonly observed misuse, especially in young type 1 diabetes patients. Potential insulin underdelivery was evaluated using five prefilled insulin pens (lispro Kwikpen(®) [Eli Lilly, Indianapolis, IN], aspart Flexpen(®) [Novo Nordisk, Bagsvaerd, Denmark], glulisine Solostar(®) [Sanofi, Paris, France], detemir Flexpen(®) [Novo Nordisk], and glargine Solostar(®) [Sanofi]) and three reusable insulin pens (Humapen(®) Luxura HD with lispro cartridge [Eli Lilly], Novopen(®) Echo with aspart and detemir cartridge [Novo Nordisk], and JuniorSTAR(®) with glulisine and glargine cartridge [Sanofi]) in a laboratory. For each pen and insulin, we simulated premature needle withdrawal 2 and 3 s after an insulin injection of 5 and 10 units, respectively. With prefilled pens, mean potential insulin underdelivery was 0.43±0.30 and 0.44±0.32 units after injection of 5 and 10 units, respectively. With reusable pens, mean potential insulin underdelivery was lower (0.29±0.13 and 0.29±0.12 units after injection of 5 and 10 units, respectively; P<0.001). The results were heterogeneous across pens, ranging from 2.6%/1.6% to 20.2%/8.6% of the selected insulin dose for prefilled/reusable pens, respectively (P<0.001). Potential insulin underdelivery varies across prefilled and reusable insulin pens but may represent up to one-fifth of the total injected dose. Clinicians should be aware of the potential consequences of premature needle withdrawal and should reinforce insulin injection education.

Statistical auditing of toxicology reports.

PubMed

Deaton, R R; Obenchain, R L

1994-06-01

Statistical auditing is a new report review process used by the quality assurance unit at Eli Lilly and Co. Statistical auditing allows the auditor to review the process by which the report was generated, as opposed to the process by which the data was generated. We have the flexibility to use different sampling techniques and still obtain thorough coverage of the report data. By properly implementing our auditing process, we can work smarter rather than harder and continue to help our customers increase the quality of their products (reports). Statistical auditing is helping our quality assurance unit meet our customers' need, while maintaining or increasing the quality of our regulatory obligations.

The current status of immunotoxins: an overview of experimental and clinical studies as presented at the Third International Symposium on Immunotoxins.

PubMed

Uckun, F M; Frankel, A

1993-02-01

The Third International Symposium on Immunotoxins was held on June 19-21, 1992 in Orlando, Florida. This symposium was sponsored by NATO, NIH, Pierce Chemical Company, Walt Disney Cancer Institute at Florida Hospital, Duke Comprehensive Cancer Center, Xoma, Immunogen, Seragen, Bristol-Myers Squibb, Chiron, Ortho Biotech, Upjohn, Merck Sharp & Dohme Research Laboratories, Abbot Laboratories, Lilly Research Laboratories, and Evans & Sutherland. The Pierce Immunotoxin Award which recognizes outstanding contributions to immunotoxin research and development, was presented to Drs David FitzGerald, Fatih Uckun, David Eisenberg, and Ira Wool, for their contributions to the immunotoxin field.

[Biopsychosocial understanding of human sexuality. Prerequisite for diagnostics and treatment in sexual medicine].

PubMed

Beier, K M

2006-08-01

Sexual medicine is a subdiscipline of clinical medicine that deals with human sexuality and disorders. Sexuality eludes a unilateral definition. As a biologically, psychologically, and socially determined experience dimension of the human being, its individual form depends on biological factors and developments in the person's life. Moreover, sexuality exhibits different dimensions--lust, reproduction, and relationship--that are indeed closely interrelated. For this reason, directing therapy at only one of these dimensions is not adequate. All human beings are programmed toward fulfillment of elementary biopsychosocial needs such as acceptance, closeness, warmth, and security. If these basic needs are shortchanged in terms of fulfillment, all sorts of restrictions in the quality of life ensue, even to the point of resultant disorders of sexual function. Treatment then approaches the roots when it does not center on the sexual dysfunction but rather on the underlying frustrated relationship of the partners. Syndyastic sexual therapy is an important treatment method in sexual medicine.

Hypoglycemic depression of hepatic phagocytosis in vivo and in the in situ perfused rat liver.

PubMed

Kober, P M; Filkins, J P

1981-01-01

Depression of the phagocytic function of the reticuloendothelial system (RES) during endotoxic hypoglycemia has been implicated in the pathogenesis of endotoxin shock. The present study evaluated the in vivo effects of hypoglycemia on RES function and assessed the effects of an vivo bout of hypoglycemia on phagocytosis in the in situ perfused rat liver. Hypoglycemia was produced in male Holtzman rats using either 1 U of regular insulin (RI) (ILETIN, Lilly) or 0.75 U of long-acting insulin (LAI) (85% LENTE/15% ULTRALENTE, Lilly). RES function was quantitated by intravascular clearance of 8 mg/100 gm body weight colloidal carbon (CC). Two hr after RI and 2.5 hr after LAI, the intravascular halftimes of CC clearance were 19 +/- 2 min (N = 22) and 18 +/- 1 min (N = 19), respectively, as compared to control, 11.3 +/- 0.4 min (N = 53, P less than 0.001). The corresponding plasma glucose (PG) levels were 95 +/- 2 mg/dl in control, 14.4 +/- 0.9 for the RI group, and 17 +/- 1 for LAI. Two hr after RI, livers were perfused for 10 min in situ with 50 mg/liter CC in saline 5% rat serum. PG for control liver donors were 90 +/- 3 mg/dl, while those for hypoglycemic liver donors were 15 +/- 2. CC uptake was decreased from 22 micrograms/min/gm liver in the control (+ serum, n = 19) to 11 +/- 2 in hypoglycemia livers (N = 6); no effect of serum on hypoglycemic depression of the RES was seen. There were no differences in flow rates in the 2 groups. These results indicate that hypoglycemia directly impairs RES function and that the in vivo depression of intravascular clearance is not related to either the presence or absence of serum factors or total hepatic blood flow. Thus, the characteristic hypoglycemia of endotoxin shock may contribute to RES depression and the lethal shock syndrome.

Subgrid Scale Modeling in Solar Convection Simulations using the ASH Code

NASA Technical Reports Server (NTRS)

Young, Y.-N.; Miesch, M.; Mansour, N. N.

2003-01-01

The turbulent solar convection zone has remained one of the most challenging and important subjects in physics. Understanding the complex dynamics in the solar con- vection zone is crucial for gaining insight into the solar dynamo problem. Many solar observatories have generated revealing data with great details of large scale motions in the solar convection zone. For example, a strong di erential rotation is observed: the angular rotation is observed to be faster at the equator than near the poles not only near the solar surface, but also deep in the convection zone. On the other hand, due to the wide range of dynamical scales of turbulence in the solar convection zone, both theory and simulation have limited success. Thus, cutting edge solar models and numerical simulations of the solar convection zone have focused more narrowly on a few key features of the solar convection zone, such as the time-averaged di erential rotation. For example, Brun & Toomre (2002) report computational finding of differential rotation in an anelastic model for solar convection. A critical shortcoming in this model is that the viscous dissipation is based on application of mixing length theory to stellar dynamics with some ad hoc parameter tuning. The goal of our work is to implement the subgrid scale model developed at CTR into the solar simulation code and examine how the differential rotation will be a affected as a result. Specifically, we implement a Smagorinsky-Lilly subgrid scale model into the ASH (anelastic spherical harmonic) code developed over the years by various authors. This paper is organized as follows. In x2 we briefly formulate the anelastic system that describes the solar convection. In x3 we formulate the Smagorinsky-Lilly subgrid scale model for unstably stratifed convection. We then present some preliminary results in x4, where we also provide some conclusions and future directions.

Efficacy and Safety Extrapolation Analyses for Atomoxetine in Young Children with Attention-Deficit/Hyperactivity Disorder.

PubMed

Upadhyaya, Himanshu; Kratochvil, Christopher; Ghuman, Jaswinder; Camporeale, Angelo; Lipsius, Sarah; D'Souza, Deborah; Tanaka, Yoko

2015-12-01

This extrapolation analysis qualitatively compared the efficacy and safety profile of atomoxetine from Lilly clinical trial data in 6-7-year-old patients with attention-deficit/hyperactivity disorder (ADHD) with that of published literature in 4-5-year-old patients with ADHD (two open-label [4-5-year-old patients] and one placebo-controlled study [5-year-old patients]). The main efficacy analyses included placebo-controlled Lilly data and the placebo-controlled external study (5-year-old patients) data. The primary efficacy variables used in these studies were the ADHD Rating Scale-IV Parent Version, Investigator Administered (ADHD-RS-IV-Parent:Inv) total score, or the Swanson, Nolan and Pelham (SNAP-IV) scale score. Safety analyses included treatment-emergent adverse events (TEAEs) and vital signs. Descriptive statistics (means, percentages) are presented. Acute atomoxetine treatment improved core ADHD symptoms in both 6-7-year-old patients (n=565) and 5-year-old patients (n=37) (treatment effect: -10.16 and -7.42). In an analysis of placebo-controlled groups, the mean duration of exposure to atomoxetine was ∼ 7 weeks for 6-7-year-old patients and 9 weeks for 5-year-old patients. Decreased appetite was the most common TEAE in atomoxetine-treated patients. The TEAEs observed at a higher rate in 5-year-old versus 6-7-year-old patients were irritability (36.8% vs. 3.6%) and other mood-related events (6.9% each vs. <3.0%). Blood pressure and pulse increased in both 4-5-year-old patients and 6-7-year-old patients, whereas a weight increase was seen only in the 6-7-year-old patients. Although limited by the small sample size of the external studies, these analyses suggest that in 5-year-old patients with ADHD, atomoxetine may improve ADHD symptoms, but possibly to a lesser extent than in older children, with some adverse events occurring at a higher rate in 5-year-old patients.

The role of GLP-1 mimetics and basal insulin analogues in type 2 diabetes mellitus: guidance from studies of liraglutide.

PubMed

Barnett, A H

2012-04-01

In people with type 2 diabetes mellitus (T2DM), the incretin effect is reduced, but the recent advent of dipeptidyl peptidase-4 inhibitors and glucagon-like peptide (GLP)-1 agonists/analogues has enabled restoration of at least some of the function of the incretin system, with accompanying improvements in glycaemic control. Two GLP-1 receptor agonists/analogues are currently approved for the treatment of T2DM-exenatide (Byetta®, Eli Lilly & Co., Indianapolis, IN, US) and liraglutide (Victoza®, Novo Nordisk, Bagsvaerd, Denmark); a once-weekly formulation of exenatide (Bydureon®, Eli Lilly & Co.) has also been approved by the European Medicines Agency. The National Institute for Health and Clinical Excellence (NICE) has recently published guidance on the use of liraglutide in T2DM, based on evidence from the Liraglutide Effect and Action in Diabetes (LEAD) Phase III trial programme, which compared liraglutide with existing glucose-lowering therapies, such as exenatide and insulin glargine. The LEAD programme reported HbA1c reductions from 0.8 to 1.5% with liraglutide (1.2 and 1.8 mg), accompanied by low rates of hypoglycaemia and some weight loss; side effects were primarily gastrointestinal in nature (e.g. nausea and diarrhoea). Based on the findings of the LEAD studies and the NICE recommendation, liraglutide now represents an important therapy widely available in the UK for certain patient groups, including those with a body mass index (BMI) ≥35.0 kg/m(2) , and patients with a BMI <35 kg/m(2) who are considered unsuitable for insulin and are failing to meet targets for glycaemic control with oral agents. NICE guidelines still suggest that most patients without considerable obesity (BMI <35 kg/m(2) ) are probably best managed using insulin therapy. Evidence also suggests a future role for GLP-1 mimetics in combination with basal insulin. © 2011 Blackwell Publishing Ltd.

The role of GLP-1 mimetics and basal insulin analogues in type 2 diabetes mellitus: guidance from studies of liraglutide

PubMed Central

Barnett, A H

2012-01-01

In people with type 2 diabetes mellitus (T2DM), the incretin effect is reduced, but the recent advent of dipeptidyl peptidase-4 inhibitors and glucagon-like peptide (GLP)-1 agonists/analogues has enabled restoration of at least some of the function of the incretin system, with accompanying improvements in glycaemic control. Two GLP-1 receptor agonists/analogues are currently approved for the treatment of T2DM—exenatide (Byetta®, Eli Lilly & Co., Indianapolis, IN, US) and liraglutide (Victoza®, Novo Nordisk, Bagsvaerd, Denmark); a once-weekly formulation of exenatide (Bydureon®, Eli Lilly & Co.) has also been approved by the European Medicines Agency. The National Institute for Health and Clinical Excellence (NICE) has recently published guidance on the use of liraglutide in T2DM, based on evidence from the Liraglutide Effect and Action in Diabetes (LEAD) Phase III trial programme, which compared liraglutide with existing glucose-lowering therapies, such as exenatide and insulin glargine. The LEAD programme reported HbA1c reductions from 0.8 to 1.5% with liraglutide (1.2 and 1.8 mg), accompanied by low rates of hypoglycaemia and some weight loss; side effects were primarily gastrointestinal in nature (e.g. nausea and diarrhoea). Based on the findings of the LEAD studies and the NICE recommendation, liraglutide now represents an important therapy widely available in the UK for certain patient groups, including those with a body mass index (BMI) ≥35.0 kg/m2, and patients with a BMI <35 kg/m2 who are considered unsuitable for insulin and are failing to meet targets for glycaemic control with oral agents. NICE guidelines still suggest that most patients without considerable obesity (BMI <35 kg/m2) are probably best managed using insulin therapy. Evidence also suggests a future role for GLP-1 mimetics in combination with basal insulin. PMID:22051096

Industrial demand side management: A status report

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

Hopkins, M.F.; Conger, R.L.; Foley, T.J.

This report provides an overview of and rationale for industrial demand side management (DSM) programs. Benefits and barriers are described, and data from the Manufacturing Energy Consumption Survey are used to estimate potential energy savings in kilowatt hours. The report presents types and examples of programs and explores elements of successful programs. Two in-depth case studies (from Boise Cascade and Eli Lilly and Company) illustrate two types of effective DSM programs. Interviews with staff from state public utility commissions indicate the current thinking about the status and future of industrial DSM programs. A comprehensive bibliography is included, technical assistance programsmore » are listed and described, and a methodology for evaluating potential or actual savings from projects is delineated.« less

Patent border wars: defining the boundary between scientific discoveries and patentable inventions.

PubMed

Holman, Christopher M

2007-12-01

Drawing an appropriate boundary between unpatentable natural phenomena and patentable inventions is crucial in preventing the patent laws from unduly restricting access to fundamental scientific discoveries. Some would argue that, particularly in the U.S., patents are being issued that purport to claim a novel product or process but that, in effect, encompass any practical application of a fundamental biological principle. Examples include gene patents, which Congress is considering banning, and patents relating to biological correlations and pathways, such as the patents at issue in the headline-grabbing LabCorp v. Metabolite and Ariad v. Eli Lilly litigations. In view of the mounting concern, it seems likely that Congress and/or the courts will address the issue, and perhaps substantially shift the boundary.

Dose accuracy and injection force dynamics of a novel disposable insulin pen.

PubMed

Clarke, Alastair; Spollett, Geralyn

2007-03-01

SoloStar (sanofi-aventis) is a new, disposable insulin pen for the administration of insulin glargine (Lantus, sanofi-aventis) or insulin glulisine (Apidra, sanofi-aventis). SoloStar was developed to address a wide range of patient needs and demonstrates advancement over previous devices, owing to its appropriate combination of ergonomically-tested and mechanically improved features. The authors report the results of key investigations carried out by sanofi-aventis as part of the SoloStar development plan, including dose accuracy and injection force testing. Comparisons between SoloStar and two commonly used pens, FlexPen (Novo Nordisk) and the Humulin/Humalog pen (Eli Lilly) establish SoloStar as a state of the art pen that is suitable for most patients with diabetes.

Stoicism, the physician, and care of medical outliers

PubMed Central

Papadimos, Thomas J

2004-01-01

Background Medical outliers present a medical, psychological, social, and economic challenge to the physicians who care for them. The determinism of Stoic thought is explored as an intellectual basis for the pursuit of a correct mental attitude that will provide aid and comfort to physicians who care for medical outliers, thus fostering continued physician engagement in their care. Discussion The Stoic topics of good, the preferable, the morally indifferent, living consistently, and appropriate actions are reviewed. Furthermore, Zeno's cardinal virtues of Justice, Temperance, Bravery, and Wisdom are addressed, as are the Stoic passions of fear, lust, mental pain, and mental pleasure. These concepts must be understood by physicians if they are to comprehend and accept the Stoic view as it relates to having the proper attitude when caring for those with long-term and/or costly illnesses. Summary Practicing physicians, especially those that are hospital based, and most assuredly those practicing critical care medicine, will be emotionally challenged by the medical outlier. A Stoic approach to such a social and psychological burden may be of benefit. PMID:15588293

Cross-cultural decoding of positive and negative non-linguistic emotion vocalizations.

PubMed

Laukka, Petri; Elfenbein, Hillary Anger; Söder, Nela; Nordström, Henrik; Althoff, Jean; Chui, Wanda; Iraki, Frederick K; Rockstuhl, Thomas; Thingujam, Nutankumar S

2013-01-01

Which emotions are associated with universally recognized non-verbal signals?We address this issue by examining how reliably non-linguistic vocalizations (affect bursts) can convey emotions across cultures. Actors from India, Kenya, Singapore, and USA were instructed to produce vocalizations that would convey nine positive and nine negative emotions to listeners. The vocalizations were judged by Swedish listeners using a within-valence forced-choice procedure, where positive and negative emotions were judged in separate experiments. Results showed that listeners could recognize a wide range of positive and negative emotions with accuracy above chance. For positive emotions, we observed the highest recognition rates for relief, followed by lust, interest, serenity and positive surprise, with affection and pride receiving the lowest recognition rates. Anger, disgust, fear, sadness, and negative surprise received the highest recognition rates for negative emotions, with the lowest rates observed for guilt and shame. By way of summary, results showed that the voice can reveal both basic emotions and several positive emotions other than happiness across cultures, but self-conscious emotions such as guilt, pride, and shame seem not to be well recognized from non-linguistic vocalizations.

The "real world" barriers and solutions to Candida vaccine patent prosecutions

PubMed Central

Wang, Shyh-Jen

2012-01-01

The US Patent and Trademark Office (USPTO) adopts recent patent courts’ opinions (such as KSR In re Fisher and Ariad v. Lilly) in patent examinations, which would certainly create barriers to biotech patent prosecution. To identify the barriers to Candida vaccine patent prosecution, we analyzed 99 US-granted patents from January 2001 to May 2012 related to Candida vaccines. The rejections were based on factors that included obviousness, novelty, indefiniteness, double patenting, enablement, written description and utility. Based on this investigation, we find that some of these rejections were actually avoidable, and then further provide workable solutions to avoid some of the barriers, especially those related to patentability. These principles recited in this study should also be applicable to other fields of vaccines and immunotherapeutics. PMID:22894949

Milky J “Hubble Gotchu" of Late Night with Jimmy Fallon visits Goddard

NASA Image and Video Library

2017-12-08

Fans of 'Late Night with Jimmy Fallon' know the setup: A guy in a Yankees jacket shows off Hubble images and shouts to the audience that, 'Hubble gotchu!' Monday night's episode showcased footage shot right here at Goddard Space Flight Center. Left to Right: Phil Driggers, Katie Lilly, Milky J “Hubble Gotchu”, Mike Menzel, Amber Straughn, Ray Lundquist. Read more about Milky J's visit here: geeked.gsfc.nasa.gov/?p=2066 NASA Goddard Space Flight Center is home to the nation's largest organization of combined scientists, engineers and technologists that build spacecraft, instruments and new technology to study the Earth, the sun, our solar system, and the universe. Follow us on Twitter Join us on Facebook Credit: NASA/Goddard Space Flight Center/Chris Gun

The insulin secretory action of novel polycyclic guanidines: discovery through open innovation phenotypic screening, and exploration of structure-activity relationships.

PubMed

Shaghafi, Michael B; Barrett, David G; Willard, Francis S; Overman, Larry E

2014-02-15

We report the discovery of the glucose-dependent insulin secretogogue activity of a novel class of polycyclic guanidines through phenotypic screening as part of the Lilly Open Innovation Drug Discovery platform. Three compounds from the University of California, Irvine, 1-3, having the 3-arylhexahydropyrrolo[1,2-c]pyrimidin-1-amine scaffold acted as insulin secretagogues under high, but not low, glucose conditions. Exploration of the structure-activity relationship around the scaffold demonstrated the key role of the guanidine moiety, as well as the importance of two lipophilic regions, and led to the identification of 9h, which stimulated insulin secretion in isolated rat pancreatic islets in a glucose-dependent manner. Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.

Managing laboratory automation in a changing pharmaceutical industry

PubMed Central

Rutherford, Michael L.

1995-01-01

The health care reform movement in the USA and increased requirements by regulatory agencies continue to have a major impact on the pharmaceutical industry and the laboratory. Laboratory management is expected to improve effciency by providing more analytical results at a lower cost, increasing customer service, reducing cycle time, while ensuring accurate results and more effective use of their staff. To achieve these expectations, many laboratories are using robotics and automated work stations. Establishing automated systems presents many challenges for laboratory management, including project and hardware selection, budget justification, implementation, validation, training, and support. To address these management challenges, the rationale for project selection and implementation, the obstacles encountered, project outcome, and learning points for several automated systems recently implemented in the Quality Control Laboratories at Eli Lilly are presented. PMID:18925014

Humalog(®) KwikPen™: an insulin-injecting pen designed for ease of use.

PubMed

Schwartz, Sherwyn L; Ignaut, Debra A; Bodie, Jennifer N

2010-11-01

Insulin pens offer significant benefits over vial and syringe injections for patients with diabetes who require insulin therapy. Insulin pens are more discreet, easier for patients to hold and inject, and provide better dosing accuracy than vial and syringe injections. The Humalog(®) KwikPen™ (prefilled insulin lispro [Humalog] pen, Eli Lilly and Company, Indianapolis, IN, USA) is a prefilled insulin pen highly rated by patients for ease of use in injections, and has been preferred by patients to both a comparable insulin pen and to vial and syringe injections in comparator studies. Together with an engineering study demonstrating smoother injections and reduced dosing error versus a comparator pen, recent evidence demonstrates the Humalog KwikPen device is an accurate, easy-to-use, patient-preferred insulin pen.

The Budget Impact of Including Necitumumab on the Formulary for First-Line Treatment of Metastatic Squamous Non-Small Cell Lung Cancer: U.S. Commercial Payer and Medicare Perspectives.

PubMed

Bly, Christopher A; Molife, Cliff; Brown, Jacqueline; Tawney, Mahesh K; Carter, Gebra Cuyun; Cinfio, Frank N; Klein, Robert W

2018-06-01

Necitumumab (Neci) was the first biologic approved by the FDA for use in combination with gemcitabine and cisplatin (Neci + GCis) in first-line treatment of metastatic squamous non-small cell lung cancer (msqNSCLC). The potential financial impact on a health plan of adding Neci + GCis to drug formularies may be important to value-based decision makers in the United States, given ever-tightening budget constraints. To estimate the budget impact of introducing Neci + GCis for first-line treatment of msqNSCLC from U.S. commercial and Medicare payer perspectives. The budget impact model estimates the costs of msqNSCLC before and after adoption of Neci + GCis in hypothetical U.S. commercial and Medicare health plans over a 3-year time horizon. The eligible patient population was estimated from U.S. epidemiology statistics. Clinical data were obtained from randomized clinical trials, U.S. prescribing information, and clinical guidelines. Market share projections were based on market research data. Cost data were obtained from online sources and published literature. The incremental aggregate annual health plan, per-patient-per-year (PPPY), and per-member-per-month (PMPM) costs were estimated in 2015 U.S. dollars. One-way sensitivity analyses were conducted to assess the effect of model parameters on results. In a hypothetical 1,000,000-member commercial health plan with an estimated population of 30 msqNSCLC patients receiving first-line chemotherapy, the introduction of Neci + GCis at an initial market share of approximately 5% had an overall year 1 incremental budget impact of $88,394 ($3,177 PPPY, $0.007 PMPM), representing a 2.9% cost increase and reaching $304,079 ($10,397 PPPY, $0.025 PMPM) or a 7.4% cost increase at a market share of 14.7% in year 3. This increase in total costs was largely attributable to Neci drug costs and, in part, due to longer survival and treatment duration for patients treated with Neci+GCis. Overall, treatment costs increased by $81,812 (13.5%), and disease costs increased by $7,951 (0.4%), whereas adverse event costs decreased by $1,368 (0.5%) in year 1. From the Medicare perspective, the overall year 1 incremental budget impact was $438,056 ($0.037 PMPM, $3,112 PPPY), representing a 3.0% cost increase. The higher incremental budget in Medicare, compared with commercial plans, was due to higher msqNSCLC incidence in the older Medicare patients (154 vs. 30 patients, respectively). Results were most sensitive to Neci drug costs. Based on projected market shares, coverage for first-line therapy with Neci + GCis appeared to modestly affect overall U.S. health care budgets for msqNSCLC-related care. Given the small eligible patient population, the PMPM budgetary impact on a commercial health plan of reimbursing Neci + GCis in the first year was less than $0.01, rising with increased use of Neci + GCis to $0.025 in the third year. The real-world effect of Neci + GCis needs to be evaluated to validate this analysis; however, these findings may help policymakers in making coverage decisions for Neci + GCis. This study was funded by Eli Lilly and Company. Molife, Brown, Tawney, and Cuyun Carter are equity holders and employees of Eli Lilly and Company. Bly, Cinfio, and Klein are employees of Medical Decision Modeling, which received funding from Eli Lilly and Company to conduct this research and prepare this manuscript.

Economic Impact of Treatment Duration and Persistence with Basal Insulin in Previously Insulin-Naive Users.

PubMed

Kalirai, Samaneh; Duan, Ran; Liu, Dongju; Reed, Beverly L

2017-03-01

Although insulin is a well-established therapy that is associated with improved clinical outcomes, adherence and persistence with insulin regimens are poor in patients with type 2 diabetes mellitus (T2DM). Diabetes-related health care costs and the impact of insulin persistence patterns on these health care costs have been previously studied; however, these aspects of insulin therapy have limited data beyond the first year of use and have not been characterized among patients previously naive to basal insulin. To (a) describe and compare medical- and pharmacy-related costs, health care resource utilization, and comorbidities and complications during the initial year and second (experienced) year of basal insulin therapy, and (b) describe and compare the impact of continuous versus interrupted basal insulin use during each year. This was a retrospective observational database analysis using claims from multiple U.S. commercial health plans (Truven Health MarketScan) in previously insulin-naive patients with T2DM who were initiated on basal insulin. Data collected included all-cause and diabetes-related medical and pharmacy costs, health care resource utilization (i.e., number and type of outpatient visits, hospitalization, emergency department [ED] visits), medication use, and preselected comorbidities and complications. This cost analysis described and compared health care costs and resource use between the initial and experienced years and further compared health care costs and resource use between continuers and interrupters within each of those years. A total of 23,645 patients were included in the analysis; 12,224 were classified as continuers and 11,421 were classified as interrupters. Among all patients, mean increases from the initial year to the experienced year were observed for all-cause medical costs ($12,690-$13,408; P = 0.048), all-cause pharmacy costs ($6,253-$6,559; P < 0.001), and all-cause health care costs ($18,943-$19,967; P = 0.006), after adjusting for inflation. All-cause pharmacy costs were significantly higher for continuers versus interrupters, but total diabetes-related medical care costs, all-cause ED costs, and all-cause medical costs were significantly lower, resulting in similar all-cause health care costs between continuers and interrupters in both the initial and experienced years. Among all patients, diabetes-related inpatient visits and outpatient primary care physician (PCP) visits, total medical inpatient visits, and total medical outpatient PCP visits were significantly higher in the initial year than in the experienced year; however, there were fewer diabetes-related ED visits in the initial year. Initiation of basal insulin appears to be associated with increased health care costs, and treatment persistence pattern (continuers vs. interrupters) is further correlated with health care expenditures. Although associated with decreased pharmacy costs, interruption of therapy increases medical costs, underscoring the importance of addressing persistence to therapy. This study was funded by Eli Lilly and Company and Boehringer Ingelheim. Eli Lilly reviewed and approved this manuscript for submission. All the authors are employees and minor shareholders of Eli Lilly and Company. Study concept and design were contributed by Kalirai, Duan, and Reed. Duan and Liu collected the data, and data interpretation was performed by Kalirai. The manuscript was written by all the authors and revised by Kalirai.

Efficacy and Safety Extrapolation Analyses for Atomoxetine in Young Children with Attention-Deficit/Hyperactivity Disorder

PubMed Central

Kratochvil, Christopher; Ghuman, Jaswinder; Camporeale, Angelo; Lipsius, Sarah; D'Souza, Deborah; Tanaka, Yoko

2015-01-01

Abstract Objectives: This extrapolation analysis qualitatively compared the efficacy and safety profile of atomoxetine from Lilly clinical trial data in 6–7-year-old patients with attention-deficit/hyperactivity disorder (ADHD) with that of published literature in 4–5-year-old patients with ADHD (two open-label [4–5-year-old patients] and one placebo-controlled study [5-year-old patients]). Methods: The main efficacy analyses included placebo-controlled Lilly data and the placebo-controlled external study (5-year-old patients) data. The primary efficacy variables used in these studies were the ADHD Rating Scale-IV Parent Version, Investigator Administered (ADHD-RS-IV-Parent:Inv) total score, or the Swanson, Nolan and Pelham (SNAP-IV) scale score. Safety analyses included treatment-emergent adverse events (TEAEs) and vital signs. Descriptive statistics (means, percentages) are presented. Results: Acute atomoxetine treatment improved core ADHD symptoms in both 6–7-year-old patients (n=565) and 5-year-old patients (n=37) (treatment effect: −10.16 and −7.42). In an analysis of placebo-controlled groups, the mean duration of exposure to atomoxetine was ∼7 weeks for 6–7-year-old patients and 9 weeks for 5-year-old patients. Decreased appetite was the most common TEAE in atomoxetine-treated patients. The TEAEs observed at a higher rate in 5-year-old versus 6–7-year-old patients were irritability (36.8% vs. 3.6%) and other mood-related events (6.9% each vs. <3.0%). Blood pressure and pulse increased in both 4–5-year-old patients and 6–7-year-old patients, whereas a weight increase was seen only in the 6–7-year-old patients. Conclusions: Although limited by the small sample size of the external studies, these analyses suggest that in 5-year-old patients with ADHD, atomoxetine may improve ADHD symptoms, but possibly to a lesser extent than in older children, with some adverse events occurring at a higher rate in 5-year-old patients. PMID:25265343

The "real world" barriers and solutions to Candida vaccine patent prosecutions: an analysis of U.S. Patent and Trademark Office actions on related applications.

PubMed

Wang, Shyh-Jen

2012-10-01

The US Patent and Trademark Office (USPTO) adopts recent patent courts' opinions (such as KSR In re Fisher and Ariad v. Lilly) in patent examinations, which would certainly create barriers to biotech patent prosecution. To identify the barriers to Candida vaccine patent prosecution, we analyzed 99 US-granted patents from January 2001 to May 2012 related to Candida vaccines. The rejections were based on factors that included obviousness, novelty, indefiniteness, double patenting, enablement, written description and utility. Based on this investigation, we find that some of these rejections were actually avoidable, and then further provide workable solutions to avoid some of the barriers, especially those related to patentability. These principles recited in this study should also be applicable to other fields of vaccines and immunotherapeutics.

Cessna UC–78 Bobcat at the Aircraft Engine Research Laboratory

NASA Image and Video Library

1943-10-21

The Aircraft Engine Research Laboratory acquired the five-seat Cessna UC–78 in March 1943 to maintain the proficiency of its pilots. The UC–78 was referred to as the “Bamboo Bomber” because of its wooden wings and tail and its fabric-covered steel body. The aircraft was produced in 1939 for civilian use, but the military soon began ordering them as training aircraft. The military also began using the aircraft for personnel transport. Cessna produced over 4600 of the aircraft for the military during World War II. The National Advisory Committee for Aeronautics’ (NACA) pilot Howard Lilly flew the UC–78 extensively during its residency in Cleveland. The aircraft was used for ferrying staff members to nearby locations and helping the pilots keep their flying hours up. The UC–78 was transferred in October 1945.

Measuring the effectiveness and impact of an open innovation platform.

PubMed

Carroll, Glenn P; Srivastava, Sanjay; Volini, Adam S; Piñeiro-Núñez, Marta M; Vetman, Tatiana

2017-05-01

Today, most pharmaceutical companies complement their traditional R&D models with some variation on the Open Innovation (OI) approach in an effort to better access global scientific talent, ideas and hypotheses. Traditional performance indicators that measure economic returns from R&D through commercialization are often not applicable to the practical assessment of these OI approaches, particularly within the context of early drug discovery. This leaves OI programs focused on early R&D without a standard assessment framework from which to evaluate overall performance. This paper proposes a practical dashboard for such assessment, encompassing quantitative and qualitative elements, to enable decision-making and improvement of future performance. The use of this dashboard is illustrated using real-time data from the Lilly Open Innovation Drug Discovery (OIDD) program. Copyright © 2017 The Author(s). Published by Elsevier Ltd.. All rights reserved.

Determination of the Period of Binary Asteroid Systems

NASA Astrophysics Data System (ADS)

Lust, Nathaniel B.; Britt, D. T.

2008-09-01

In the study of asteroids, binary pairs offer a unique window of study. By observing these systems and determining the period of the secondary, it is possible to determine system mass (e.g. Pravec and Hahn 1997; Ryan et al., 2004). With mass and volume, properties such as bulk density and porosity can be derived. At the University of Central Florida we have begun a binary asteroid hunt, in conjunction with the Prague consortium, in order to identify new binary candidates and to better constrain data on known pairs. All of the observations are collected on campus using a 0.5meter f/8.1 Ritchey-Chretien telescope with a SBIG STL-6303E detector. For our first test target we observed the known binary asteroid 107 Camila over a period of six days for approximately six to eight hours a night. The data is then processed using an open source python algorithm developed by Nate Lust. The data is read in, reduced, and compared to a standard star. Once the light curve was generated we make use of the CLEAN algorithm, originally developed by Hogbom (1974), to extract meaningful periods from the light curve.

Volatile organic compounds in the nation's ground water and drinking-water supply wells

USGS Publications Warehouse

Zogorski, John S.; Carter, Janet M.; Ivahnenko, Tamara; Lapham, Wayne W.; Moran, Michael J.; Rowe, Barbara L.; Squillace, Paul J.; Toccalino, Patricia L.

2006-01-01

This national assessment of 55 volatile organic compounds (VOCs) in ground water gives emphasis to the occurrence of VOCs in aquifers that are used as an important supply of drinking water. In contrast to the monitoring of VOC contamination of ground water at point-source release sites, such as landfills and leaking underground storage tanks (LUSTs), our investigations of aquifers are designed as large-scale resource assessments that provide a general characterization of water-quality conditions. Nearly all of the aquifers included in this assessment have been identified as regionally extensive aquifers or aquifer systems. The assessment of ground water (Chapter 3) included analyses of about 3,500 water samples collected during 1985-2001 from various types of wells, representing almost 100 different aquifer studies. This is the first national assessment of the occurrence of a large number of VOCs with different uses, and the assessment addresses key questions about VOCs in aquifers. The assessment also provides a foundation for subsequent decadal assessments of the U.S. Geological Survey (USGS) National Water-Quality Assessment (NAWQA) Program to ascertain long-term trends of VOC occurrence in these aquifers.

Commentary: doctors without boundaries: the ethics of teacher-student relationships in academic medicine.

PubMed

Larkin, Gregory Luke; Mello, Michael J

2010-05-01

Possessed of both instinct and intellect, physician teachers are required to be respectful exemplars of professionalism and interpersonal ethics in all environments, be it the hospital, classroom, or outside the educational setting. Sometimes, even while protecting the sanctity of the teacher-student relationship, they may surreptitiously find themselves in the throes of consensual intimacy, boundary violations, student exploitation, or other negative interpersonal and/or departmental dynamics. One may question how an academic can consistently resolve this tension and summon the temperance, humility, charity, and restraint needed to subdue lust, pride, abuse, and incontinence in the workplace. One important answer may lie in an improved understanding of the moral necessity of social cooperation, fairness, reciprocity, and respect that is constitutive of the physician-teacher role. Although normative expectations and duties have been outlined in extant codes of ethics and conduct within academic medicine, to date, few training programs currently teach faculty and residents about the ethics of appropriate pedagogic and intimate relations between teaching staff and students, interns, residents, researchers, and other trainees. This essay highlights examples from history, literature, and medical ethics as one small step toward filling this void.

'Sometimes people let love conquer them': how love, intimacy, and trust in relationships between men who have sex with men influence perceptions of sexual risk and sexual decision-making.

PubMed

Goldenberg, Tamar; Finneran, Catherine; Andes, Karen L; Stephenson, Rob

2015-01-01

Men who have sex with men account for a disproportionate burden of HIV incidence in the USA. Although much research has examined the drivers of sexual risk-taking, the emotional contexts in which men make sexual decisions has received little attention. In this three-phase, 10-week longitudinal qualitative study involving 25 gay and bisexual men, we used timeline-based interviews and quantitative web-based diaries about sexual and/or dating partners to examine how emotions influence HIV risk perceptions and sexual decision-making. Participants described love, intimacy, and trust as reducing HIV risk perceptions and facilitating engagement in condomless anal intercourse. Lust was not as linked with risk perceptions, but facilitated non condom-use through an increased willingness to engage in condomless anal intercourse, despite perceptions of risk. Results indicate that gay and bisexual men do not make sexual decisions in an emotional vacuum. Emotions influence perceptions of risk so that they do not necessarily align with biological risk factors. Emotional influences, especially the type and context of emotions, are important to consider to improve HIV prevention efforts among gay and bisexual men.

Cross-cultural decoding of positive and negative non-linguistic emotion vocalizations

PubMed Central

Laukka, Petri; Elfenbein, Hillary Anger; Söder, Nela; Nordström, Henrik; Althoff, Jean; Chui, Wanda; Iraki, Frederick K.; Rockstuhl, Thomas; Thingujam, Nutankumar S.

2013-01-01

Which emotions are associated with universally recognized non-verbal signals?We address this issue by examining how reliably non-linguistic vocalizations (affect bursts) can convey emotions across cultures. Actors from India, Kenya, Singapore, and USA were instructed to produce vocalizations that would convey nine positive and nine negative emotions to listeners. The vocalizations were judged by Swedish listeners using a within-valence forced-choice procedure, where positive and negative emotions were judged in separate experiments. Results showed that listeners could recognize a wide range of positive and negative emotions with accuracy above chance. For positive emotions, we observed the highest recognition rates for relief, followed by lust, interest, serenity and positive surprise, with affection and pride receiving the lowest recognition rates. Anger, disgust, fear, sadness, and negative surprise received the highest recognition rates for negative emotions, with the lowest rates observed for guilt and shame. By way of summary, results showed that the voice can reveal both basic emotions and several positive emotions other than happiness across cultures, but self-conscious emotions such as guilt, pride, and shame seem not to be well recognized from non-linguistic vocalizations. PMID:23914178

THE EFFECTS OF PANTOTHENIC ACID ON RESPIRATORY ACTIVITY.

PubMed

Pratt, E F; Williams, R J

1939-05-20

Experiments using the Warburg-Barcroft apparatus led to the following results and conclusions: (1) Two yeasts in three different media were strikingly stimulated in their respiration by minute amounts of pantothenic acid. (2) Nine other compounds (vitamins and other biologically important substances) were tested and found in all cases to have on the deficient G.M. yeast, lesser and in some cases no appreciable stimulative effect. Thiamin was the most effective of these compounds. Its action was shown to be different and in some ways antagonistic to that of pantothenic acid. (3) Liver extract (Lilly's Number 343) contains substances capable of speeding up respiration (and growth) to a much higher level than seems possible with known compounds. (4) Pantothenic acid was found to have a definite stimulative effect on fermentation by dialyzed maceration juice from yeast. (5) It likewise stimulated respiration of apple and potato tissue and indications of a similar effect on certain animal tissues were obtained.

An industry update: the latest news in therapeutic delivery.

PubMed

Harris, Elaine

2017-11-01

The present industry update covers the period 1-31 July 2017. Information was sourced primarily from company press releases, regulatory and patent agencies, scientific literature and various news websites. There was positive approval news this month for GlaxoSmithKline for its new self-injecting treatment for systemic lupus erythematosus but less positive news for Ocular Therapeutix, a new drug application for its treatment for postoperative ocular pain, DEXTENZA™ was rejected for a second time. Endo Pharmaceuticals agreed to withdraw its opioid formulation Opana ® Er due to abuse concerns. Collaborations for novel therapeutic delivery research were announced this month by Takeda and BioSurfaces, Catelent and Rutgers University, Lilly and Purdue University and Titan Pharmaceuticals with Walter Reed and the Southwest Research Institute. A number of companies announced significant financing deals to allow for the clinical development of products with enhanced delivery options including Sebacia and Diasome.

Inversion of Gravity and Magnetic Field Data for Tyrrhena Patera

NASA Technical Reports Server (NTRS)

Milbury, C.; Schubert, G.; Raymond, C. A.; Smrekar, S. E.

2011-01-01

Tyrrhena Patera is located to the southeast/northeast of the Isidis/Hellas impact basin. It was geologically active into the Late Amazonian, although the main edifice was formed in the Noachian(approximately 3.7-4.0 Ga). Tyrrhena Patera and the surrounding area contain gravity and magnetic anomalies that appear to be correlated. The results presented here are for the anomalies 1a and 1b (closest to Tyrrhena Patera), however other anomalies in this region have been modeled and will be presented at the conference.The Mars Global Surveyor (MGS) free-air gravity signature of Tyrrhena Patera has been studied by Kiefer, who inferred the existence of an extinct magma chamber below it. The magnetic signature has been mapped by Lillis R. J. et al., who compared electron reflectometer data, analogous to the total magnetic field, for Syrtis Major and Tyrrhena Patera and argued for demagnetization of both volcanoes.

Dissipative, forced turbulence in two-dimensional magnetohydrodynamics

NASA Technical Reports Server (NTRS)

Fyfe, D.; Montgomery, D.; Joyce, G.

1976-01-01

The equations of motion for turbulent two-dimensional magnetohydrodynamic flows are solved in the presence of finite viscosity and resistivity, for the case in which external forces (mechanical and/or magnetic) act on the fluid. The goal is to verify the existence of a magnetohydrodynamic dynamo effect which is represented mathematically by a substantial back-transfer of mean square vector potential to the longest allowed Fourier wavelengths. External forces consisting of a random part plus a fraction of the value at the previous time step are employed, after the manner of Lilly for the Navier-Stokes case. The regime explored is that for which the mechanical and magnetic Reynolds numbers are in the region of 100 to 1000. The conclusions are that mechanical forcing terms alone cannot lead to dynamo action, but that dynamo action can result from either magnetic forcing terms or from both mechanical and magnetic forcing terms simultaneously.

Vegetative Growth of Four Strains of Hericium erinaceus Collected from Different Habitats

PubMed Central

Imtiaj, Ahmed; Jayasinghe, Chandana; Lee, Geon Woo; Shim, Mi Ja; Rho, Hyun-Su; Lee, Hyun Sook; Hur, Hyun; Lee, Min Woong; Lee, U-Youn

2008-01-01

Vegetative growth of four different strains of Hericium erinaceus was observed. The temperature suitable for optimal mycelial growth was determined to be 25℃, with growth observed in the extend temperature range of 20~30℃. The different strains of this mushroom showed distinct pH requirements for their optimum vegetative growth, with the most favorable growth observed at pH 6. Considering vegetative mycelial growth, PDA, YM, Hennerberg, Hamada, and Glucose peptone were the most favorable media, and Czapek Dox, Hoppkins, Glucose tryptone, and Lilly were the most unfavorable media for these mushroom strains. With the exception of lactose, most of the carbon sources assayed demonstrated favorable vegetative growth of H. erinaceus. For mycelial growth, the most suitable nitrogen source was alanine and the most unsuitable was histidine. Oak sawdust medium supplemented with 10~20% rice bran was the best for mycelial growth of the mushroom. PMID:23990739

Personality Influences the Relationship Between Primary Emotions and Religious/Spiritual Well-Being.

PubMed

Hiebler-Ragger, Michaela; Fuchshuber, Jürgen; Dröscher, Heidrun; Vajda, Christian; Fink, Andreas; Unterrainer, Human F

2018-01-01

The study of human emotions and personality provides valuable insights into the parameters of mental health and well-being. Affective neuroscience proposes that several levels of emotions - ranging from primary ones such as LUST or FEAR up to higher emotions such as spirituality - interact on a neural level. The present study aimed to further explore this theory. Furthermore, we hypothesized that personality - formed by bottom-up primary emotions and cortical top-down regulation - might act as a link between primary emotions and religious/spiritual well-being. A total sample of 167 (78% female) student participants completed the Affective Neuroscience Personality Scale (primary emotions), the Big Five Personality Inventory and the Multidimensional Inventory of Religious/Spiritual Well-Being (higher emotions). Correlation analyses confirmed the link between primary and higher emotions as well as their relation to personality. Further regression analyses indicated that personality dimensions mediate the relationship between primary and higher emotions. A substantial interaction between primary emotions, personality dimensions, and religious/spiritual well-being could be confirmed. From a developmental perspective, cortical top-down regulation might influence religious/spiritual well-being by forming relevant personality dimensions. Hence, CARE as well as Agreeableness seem of special importance. Future studies might focus on implications for clinical groups.

‘Sometimes people let love conquer them’: how love, intimacy, and trust in relationships between men who have sex with men influence perceptions of sexual risk and sexual decision-making

PubMed Central

Goldenberg, Tamar; Finneran, Catherine; Andes, Karen L.; Stephenson, Rob

2015-01-01

Men who have sex with men account for a disproportionate burden of HIV incidence in the USA. Although much research has examined the drivers of sexual risk-taking, the emotional contexts in which men make sexual decisions has received little attention. In this three-phase, 10-week longitudinal qualitative study involving 25 gay and bisexual men, we used timeline-based interviews and quantitative web-based diaries about sexual and/or dating partners to examine how emotions influence HIV risk perceptions and sexual decision-making. Participants described love, intimacy, and trust as reducing HIV risk perceptions and facilitating engagement in condomless anal intercourse. Lust was not as linked with risk perceptions, but facilitated non condom-use through an increased willingness to engage in condomless anal intercourse, despite perceptions of risk. Results indicate that gay and bisexual men do not make sexual decisions in an emotional vacuum. Emotions influence perceptions of risk so that they do not necessarily align with biological risk factors. Emotional influences, especially the type and context of emotions, are important to consider to improve HIV prevention efforts among gay and bisexual men. PMID:25465292

Ganzheitliche Digitalisierungsansätze im Stadtwerk: Von der Strategie bis zur Umsetzung

NASA Astrophysics Data System (ADS)

Dudenhausen, Roman; Hahn, Heike

Digitalisierung muss im Stadtwerk dazu führen, Kundenerwartungen, die heutzutage schon vielfach durch digitales Know-how und Erfahrungen geprägt sind, in einzigartiger Weise zu entsprechen - in Form digitaler Kundenkontaktpunkte, automatisierter Prozesse oder plattformbasierter Geschäftsmodelle. Eine große Rolle spielen dabei unternehmensweit nutzbare Informationen, die eine 360-Grad-Sicht auf den Kunden ermöglichen. Nur in dieser Kombination werden sich nachhaltig Wettbewerbsvorteile generieren lassen. Manch ein Kunde wird die Lust, einen Prozess zu Ende zu gehen, schon vor dem Abschluss verlieren, wenn er nicht unmittelbar und ohne die digitale Welt zu verlassen zum Ziel kommt. Eine nur "halb digitale Kundenerfahrung" wird weder zu Neugeschäft noch zur positiven emotionalen Bindung zwischen Kunden und Stadtwerk führen. Nicht zu unterschätzen sind zudem Erwartungen hinsichtlich zukünftiger Geschäftsmodelle, aus denen sich disruptive Bedrohungen für die herkömmlichen Strom- und Gasangebote ergeben werden. Erste innovative Ansätze finden sich bereits im Markt, die erahnen lassen, dass zurzeit viel diskutierte Technologien wie die Blockchain nicht mehr nur hypothetischer Natur sind. Die Auseinandersetzung mit der Digitalisierung erfolgt dabei sinnvollerweise in einem unternehmensweit abgestimmten Rahmen, der eine zielgerichtete und ganzheitliche Vorgehensweise ermöglicht.

Should condoms be available in prisons?

PubMed

1997-09-01

Worldwide, it is increasingly recognized that sex occurs in prisons and this condition promotes HIV transmission among men. It is noted that in prisons, men usually engage in consensual or forced anal sex for lust, comfort, privileges or domination. This sexual behavior is one of the riskiest sexual practices in transmitting HIV infection because of the frequent tearing of sensitive anal membranes. In view of such a serious problem, that will also impact widely on the community when prisoners are released, a multi-pronged strategy is needed. Several initiatives addressing the issue are being reviewed or implemented in various countries. In Zimbabwe, among the listed options under consideration in the draft National Policy on HIV/AIDS, the most debated policy issue is the dissemination of condoms in prison. Much public dissent has been noted, in which the fear is that this would be seen as condoning homosexuality. However, it is emphasized that the issue in prisons is not one of homosexuality, but of recognizing that many heterosexual men in prison will take the only sexual outlet available to them (in addition to masturbation). In doing so, they are at great risk of HIV infection, hence encouraging mutual or self masturbation and actively promoting condom use must be part of the response to the epidemic issue.

[The history of prostate cancer from the beginning to DaVinci].

PubMed

Hatzinger, M; Hubmann, R; Moll, F; Sohn, M

2012-07-01

For hardly any other organ can the development of medicine and technical advances in the last 150 years be so clearly illustrated as for the prostate. The history of radical prostatectomy was initially characterised by the problems in approaching this relatively difficulty accessible organ. In 1867, Theodor Billroth in Vienna performed the first partial prostatectomy via a perineal access. In 1904, Hugh Hampton Young and William Stewart Halsted at the Johns Hopkins Hospital in Baltimore / USA carried out the first successful extracapsular perineal prostatectomy and opened up a new era. In Germany, Prof. Friedrich Voelcker in Halle in 1924 developed the so-called ischiorectal prostatectomy. But it was left to Terence Millin to publish in 1945 the first series of retropubic prostatectomies. In 1952, the sacroperineal approach according to Thiermann and the sacral prostatectomy according to were introduced. Finally, in 1991 another new era in prostate surgery started with the first laparoscopic prostatectomy. This development peaked in 2011 with the presentation of the laparoscopic DaVinci prostatectomy by Binder. Originally a stepchild of urological surgery that was to be avoided whenever possible due to the fear of serious complications, the prostate has progressed in the course of time to an obscure object of lust. The stepchild has become the favorite child.

SOIL AND SEDIMENT SAMPLING METHODS | Science ...

EPA Pesticide Factsheets

The EPA Office of Solid Waste and Emergency Response's (OSWER) Office of Superfund Remediation and Technology Innovation (OSRTI) needs innovative methods and techniques to solve new and difficult sampling and analytical problems found at the numerous Superfund sites throughout the United States. Inadequate site characterization and a lack of knowledge of surface and subsurface contaminant distributions hinders EPA's ability to make the best decisions on remediation options and to conduct the most effective cleanup efforts. To assist OSWER, NERL conducts research to improve their capability to more accurately, precisely, and efficiently characterize Superfund, RCRA, LUST, oil spills, and brownfield sites and to improve their risk-based decision making capabilities, research is being conducted on improving soil and sediment sampling techniques and improving the sampling and handling of volatile organic compound (VOC) contaminated soils, among the many research programs and tasks being performed at ESD-LV.Under this task, improved sampling approaches and devices will be developed for characterizing the concentration of VOCs in soils. Current approaches and devices used today can lose up to 99% of the VOCs present in the sample due inherent weaknesses in the device and improper/inadequate collection techniques. This error generally causes decision makers to markedly underestimate the soil VOC concentrations and, therefore, to greatly underestimate the ecological

The devil is in the details: the seven deadly sins of organizing and continuing interprofessional education in the US.

PubMed

Clark, Phillip G

2011-09-01

In spite of increased calls for expanding interprofessional practice (IPP) in the US health care system to address concerns about patient safety and quality of care, there has not been a corresponding dramatic growth in interprofessional education (IPE) programs. Indeed, the history of IPE in the US has been a roller-coaster ride of gains and losses, successes and failures. Understanding why this has been so requires the development of a personal and political economy framework, based on an understanding of the structural, ideological, and economic factors and forces that characterize IPE in American higher education. Using a metaphor of the seven deadly sins (lust, pride, greed, gluttony, envy, sloth, and wrath), this discussion focuses on both things that should not be done (sins of commission) and those that should be done but are not (sins of omission) to create successful and sustainable IPE programs. Taken together, these factors help to frame a perspective on IPE that highlights the essential knowledge, attitudes, and skills needed by faculty and administrators to create, implement, and - most importantly - sustain successful programs. Implications of this framework for promoting increased IPE are discussed, particularly with respect to insuring its successful continuation into the future.

Quality of life theory III. Maslow revisited.

PubMed

Ventegodt, Søren; Merrick, Joav; Andersen, Niels Jørgen

2003-10-13

In 1962, Abraham Maslow published his book Towards a Psychology of Being, and established a theory of quality of life, which still is considered a consistent theory of quality of life. Maslow based his theory for development towards happiness and true being on the concept of human needs. He described his approach as an existentialistic psychology of self-actualization, based on personal growth. When we take more responsibility for our own life, we take more of the good qualities that we have into use, and we become more free, powerful, happy, and healthy. It seems that Maslow's concept of self-actualization can play an important role in modern medicine. As most chronic diseases often do not disappear in spite of the best biomedical treatments, it might be that the real change our patients have for betterment is understanding and living the noble path of personal development. The hidden potential for improving life really lies in helping the patient to acknowledge that his or her lust for life, his or her needs, and his or her wish to contribute, is really deep down in human existence one and the same. But you will only find this hidden meaning of life if you scrutinize your own life and existence closely enough, to come to know your innermost self.

Quality of Life Theory III. Maslow Revisited

PubMed Central

Ventegodt, Soren; Merrick, Joav; Andersen, Niels Jorgen

2003-01-01

In 1962, Abraham Maslow published his book Towards a Psychology of Being, and established a theory of quality of life, which still is considered a consistent theory of quality of life. Maslow based his theory for development towards happiness and true being on the concept of human needs. He described his approach as an existentialistic psychology of self-actualization, based on personal growth.When we take more responsibility for our own life, we take more of the good qualities that we have into use, and we become more free, powerful, happy, and healthy. It seems that Maslow's concept of self-actualization can play an important role in modern medicine. As most chronic diseases often do not disappear in spite of the best biomedical treatments, it might be that the real change our patients have for betterment is understanding and living the noble path of personal development. The hidden potential for improving life really lies in helping the patient to acknowledge that his or her lust for life, his or her needs, and his or her wish to contribute, is really deep down in human existence one and the same. But you will only find this hidden meaning of life if you scrutinize your own life and existence closely enough, to come to know your innermost self. PMID:14570995

How Does Adult Attachment Affect Human Recognition of Love-related and Sex-related Stimuli: An ERP Study

PubMed Central

Hou, Juan; Chen, Xin; Liu, Jinqun; Yao, Fangshu; Huang, Jiani; Ndasauka, Yamikani; Ma, Ru; Zhang, Yuting; Lan, Jing; Liu, Lu; Fang, Xiaoyi

2016-01-01

In the present study, we investigated the relationship among three emotion-motivation systems (adult attachment, romantic love, and sex). We recorded event-related potentials in 37 healthy volunteers who had experienced romantic love while they viewed SEX, LOVE, FRIEND, SPORT, and NEUTRAL images. We also measured adult attachment styles, level of passionate love and sexual attitudes. As expected, results showed that, firstly, response to love-related image-stimuli and sex-related image-stimuli on the electrophysiological data significantly different on N1, N2, and positive slow wave (PSW) components. Secondly, the different adult attachment styles affected individuals’ recognition processing in response to love-related and sex-related images, especially, to sex-related images. Further analysis showed that voltages elicited by fearful attachment style individuals were significantly lower than voltages elicited by secure and dismissing attachment style individuals on sex-related images at frontal sites, on N1 and N2 components. Thirdly, from behavior data, we found that adult attachment styles were not significantly related to any dimension of sexual attitudes but were significantly related to passionate love scale (PLS) total points. Thus, the behavior results were not in line with the electrophysiological results. The present study proved that adult attachment styles might mediate individuals’ lust and attraction systems. PMID:27199830

Personality Influences the Relationship Between Primary Emotions and Religious/Spiritual Well-Being

PubMed Central

Hiebler-Ragger, Michaela; Fuchshuber, Jürgen; Dröscher, Heidrun; Vajda, Christian; Fink, Andreas; Unterrainer, Human F.

2018-01-01

The study of human emotions and personality provides valuable insights into the parameters of mental health and well-being. Affective neuroscience proposes that several levels of emotions – ranging from primary ones such as LUST or FEAR up to higher emotions such as spirituality – interact on a neural level. The present study aimed to further explore this theory. Furthermore, we hypothesized that personality – formed by bottom-up primary emotions and cortical top-down regulation – might act as a link between primary emotions and religious/spiritual well-being. A total sample of 167 (78% female) student participants completed the Affective Neuroscience Personality Scale (primary emotions), the Big Five Personality Inventory and the Multidimensional Inventory of Religious/Spiritual Well-Being (higher emotions). Correlation analyses confirmed the link between primary and higher emotions as well as their relation to personality. Further regression analyses indicated that personality dimensions mediate the relationship between primary and higher emotions. A substantial interaction between primary emotions, personality dimensions, and religious/spiritual well-being could be confirmed. From a developmental perspective, cortical top-down regulation might influence religious/spiritual well-being by forming relevant personality dimensions. Hence, CARE as well as Agreeableness seem of special importance. Future studies might focus on implications for clinical groups. PMID:29615950

Primary emotional traits in patients with personality disorders.

PubMed

Karterud, Sigmund; Pedersen, Geir; Johansen, Merete; Wilberg, Theresa; Davis, Ken; Panksepp, Jaak

2016-11-01

There is a longstanding tradition that connects temperament pathology and personality disorders. Emotions are the major constituents of temperament. In mammals, seven primary emotions have been identified: SEEKING, FEAR, CARE, RAGE, SADNESS/PANIC, LUST and PLAY. The study aimed at exploring the relationship between primary emotions and personality disorders (PDs). Five hundred forty-six patients with different degrees and qualities of personality pathology, admitted to treatment in specialized PD services, were diagnosed according to Structured Clinical Interview for DSM-IV Axis II Personality Disorders, and their primary emotional profiles were assessed by the Affective Neuroscience Personality Scales. The Affective Neuroscience Personality Scales explained 19% of the variance in borderline and avoidant criteria. The DSM-IV PD categories displayed different patterns of association to the primary emotions, e.g. the borderline PD profile suggested low thresholds for RAGE and SADNESS, but on the positive side a propensity for SEEKING. In contrast, the dependent PD profile suggested a low threshold for SADNESS but a high threshold for RAGE and SEEKING. The results are promising for a more coherent and evolution-based overall theory of PDs, and the correlations found in this study indicate testable causal pathways to PDs. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

OLEM Performance Assessment Information

EPA Pesticide Factsheets

This asset includes a variety of data sets that measure the performance of Office of Land and Emergency Management (OLEM) programs in support of the Office of the Chief Financial Officer's Annual Commitment System (ACS) and Performance Evaluation Reporting System (PERS). Information is drawn from OLEM's ACRES, RCRAInfo, CERCLIS/SEMS, ICIS, and LUST4 systems, as well as input manually by authorized individuals in OLEM's program offices. Information is reviewed by OLEM program staff prior to being pushed to ACS and entered into PERS. This data asset also pulls in certain performance information input directly by Regional Office staff into ACS. Information is managed by the Performance Assessment Tool (PAT) and displayed in the PAT Dashboard.Information in this asset include:--Government Performance and Results Act (GPRA) of 1993: Measures reported for Innovations, Partnerships and Communications Office (IPCO), the Office of Brownfields and Land Revitalization (OBLR), the Office of Emergency Management (OEM), the Office of Resource Conservation and Recovery (ORCR), the Office of Superfund Remediation and Technology Innovation (OSRTI), and the Office of Underground Storage Tanks (OUST).-- Performance and Environmental Results System (PERS): Includes OLEM's information on performance results and baselines for the EPA Annual Plan and Budget.--Key Performance Indicators: OLEM has identified five KPIs that are tracked annually.--Integrated Cleanup Initiative: A pilot pe

How Does Adult Attachment Affect Human Recognition of Love-related and Sex-related Stimuli: An ERP Study.

PubMed

Hou, Juan; Chen, Xin; Liu, Jinqun; Yao, Fangshu; Huang, Jiani; Ndasauka, Yamikani; Ma, Ru; Zhang, Yuting; Lan, Jing; Liu, Lu; Fang, Xiaoyi

2016-01-01

In the present study, we investigated the relationship among three emotion-motivation systems (adult attachment, romantic love, and sex). We recorded event-related potentials in 37 healthy volunteers who had experienced romantic love while they viewed SEX, LOVE, FRIEND, SPORT, and NEUTRAL images. We also measured adult attachment styles, level of passionate love and sexual attitudes. As expected, results showed that, firstly, response to love-related image-stimuli and sex-related image-stimuli on the electrophysiological data significantly different on N1, N2, and positive slow wave (PSW) components. Secondly, the different adult attachment styles affected individuals' recognition processing in response to love-related and sex-related images, especially, to sex-related images. Further analysis showed that voltages elicited by fearful attachment style individuals were significantly lower than voltages elicited by secure and dismissing attachment style individuals on sex-related images at frontal sites, on N1 and N2 components. Thirdly, from behavior data, we found that adult attachment styles were not significantly related to any dimension of sexual attitudes but were significantly related to passionate love scale (PLS) total points. Thus, the behavior results were not in line with the electrophysiological results. The present study proved that adult attachment styles might mediate individuals' lust and attraction systems.

The Role of Chalcones in Suppression of NF-κB-Mediated Inflammation and Cancer

PubMed Central

Yadav, Vivek R.; Prasad, Sahdeo; Sung, Bokyung; Aggarwal, Bharat B.

2010-01-01

Although consumption of fruits, vegetables, spices, cereals and pulses has been associated with lower incidence of cancer and other chronic diseases, how these dietary agents and their active ingredients minimize these diseases, is not fully understood. Whether it is oranges, kawa, hops, water-lilly, locorice, wax apple or mulberry, they are all connected by a group of aromatic ketones, called chalcones (1,3-diaryl-2-propen-1-ones). Some of the most significant chalcones identified from these plants include flavokawin, butein, xanthoangelol, 4-hydroxyderricin, cardamonin, 2′,4′-dihydroxychalcone, isoliquiritigenin, isosalipurposide, and naringenin. These chalcones have been linked with immunomodulation, antibacterial, antifungal, antiviral, anti-inflammatory, antioxidant, anticancer, and antidiabetic activities. The current review, however, deals with the role of various chalcones in inflammation that controls both the immune system and tumorigenesis. Inflammatory pathways have been shown to mediate the survival, proliferation, invasion, angiogenesis and metastasis of tumors. How these chalcones modulate inflammatory pathways, tumorigenesis and immune system is the focus of this review. PMID:21184860

Current perspectives on chief residents in psychiatry.

PubMed

Warner, Christopher H; Rachal, James; Breitbach, Jill; Higgins, Michael; Warner, Carolynn; Bobo, William

2007-01-01

The authors examine qualitative data from outgoing chief residents in psychiatry from the 2004-2005 academic year to 1) determine common characteristics between programs, 2) examine the residents' perspectives on their experiences, and 3) determine their common leadership qualities. The authors sent out self-report surveys via e-mail to 89 outgoing chief residents who attended the APA/Lilly Chief Resident Executive Leadership Program. Fifty-three (60%) chief residents responded. Although most chief residents are senior residents, over 20% are in their third postgraduate year. Two-thirds of programs have more than one chief resident each year. Most chief residents believe that their "participating" leadership style, existing leadership skills, and interpersonal skills contributed to their overall positive experiences. Successfully performing duties as a chief resident entails functioning in a variety of roles and demands attention to leadership qualities of the individual. Developing existing leadership skills, clarifying expectations, and providing mentorship to chief residents will ensure successful transition into practice, and the advancement of the field of psychiatry.

Factors Associated with Adherence to and Treatment Duration of Erlotinib Among Patients with Non-Small Cell Lung Cancer.

PubMed

Hess, Lisa M; Louder, Anthony; Winfree, Katherine; Zhu, Yajun E; Oton, Ana B; Nair, Radhika

2017-06-01

In lung cancer, there is an increasing number of oral agents available for patients; however, little is known about the factors associated with adherence to and treatment duration on oral medications in non-small cell lung cancer (NSCLC). To evaluate the clinical and demographic factors associated with adherence and treatment discontinuation, respectively, to oral oncolytics among patients with NSCLC. A retrospective, claims-based analysis of the Humana Research Database supplemented with medical chart review was conducted among patients with NSCLC who started an oral oncolytic between January 1, 2008, and June 30, 2013. Patients were required to be enrolled at least 1 year before the start of oral oncolytics and have no evidence of any oral oncolytic use during this period. Logistic regression models and Cox proportional hazard models were used to identify predictors associated with medication adherence and treatment duration, respectively. Among all oral oncolytics, only the cohort starting on erlotinib had sufficient sample size (n = 1,452). A wide variety of factors were found to be associated with adherence. Low-income subsidy status, previous use of intravenous chemotherapy, and lower total baseline health care costs were significantly related to decreasing adherence (each P < 0.05). Additionally, increasing patient out-of-pocket cost was associated with decreasing adherence to erlotinib (P < 0.0001). Factors significantly related to longer treatment duration included low-income subsidy status (P < 0.001) and having Medicare insurance, (P = 0.0004), dual eligibility (Medicare and Medicaid, P = 0.007), and higher erlotinib out-of-pocket costs (P < 0.0001). There is a need for mechanisms to be in place to identify and address barriers to care. Future research should focus on evaluating and reducing any potential risk to patient outcomes that may be associated with low adherence to or shorter treatment duration on oral chemotherapy. This study was supported by funding from Eli Lilly and Company to Comprehensive Health Insights, a Humana company, as a collaborative research project involving employees of both companies. Hess, Winfree, Zhu, and Oton are employees of Eli Lilly and Company. Louder and Nair are employees of Comprehensive Health Insights, which received funding to complete this research. Study concept and design were contributed by Hess, Zhu, Winfree, and Oton. Nair and Louder collected the data, and data interpretation was performed by all the authors. The manuscript was written primarily by Hess, along with Nair, and revised by Hess, Nair, Louder, and Winfree, with assistance from Zhu and Louder.

Suicidality and aggression during antidepressant treatment: systematic review and meta-analyses based on clinical study reports.

PubMed

Sharma, Tarang; Guski, Louise Schow; Freund, Nanna; Gøtzsche, Peter C

2016-01-27

To study serious harms associated with selective serotonin and serotonin-norepinephrine reuptake inhibitors.Design Systematic review and meta-analysis. Mortality and suicidality. Secondary outcomes were aggressive behaviour and akathisia. Clinical study reports for duloxetine, fluoxetine, paroxetine, sertraline, and venlafaxine obtained from the European and UK drug regulators, and summary trial reports for duloxetine and fluoxetine from Eli Lilly's website. Double blind placebo controlled trials that contained any patient narratives or individual patient listings of harms. Two researchers extracted data independently; the outcomes were meta-analysed by Peto's exact method (fixed effect model). We included 70 trials (64,381 pages of clinical study reports) with 18,526 patients. These trials had limitations in the study design and discrepancies in reporting, which may have led to serious under-reporting of harms. For example, some outcomes appeared only in individual patient listings in appendices, which we had for only 32 trials, and we did not have case report forms for any of the trials. Differences in mortality (all deaths were in adults, odds ratio 1.28, 95% confidence interval 0.40 to 4.06), suicidality (1.21, 0.84 to 1.74), and akathisia (2.04, 0.93 to 4.48) were not significant, whereas patients taking antidepressants displayed more aggressive behaviour (1.93, 1.26 to 2.95). For adults, the odds ratios were 0.81 (0.51 to 1.28) for suicidality, 1.09 (0.55 to 2.14) for aggression, and 2.00 (0.79 to 5.04) for akathisia. The corresponding values for children and adolescents were 2.39 (1.31 to 4.33), 2.79 (1.62 to 4.81), and 2.15 (0.48 to 9.65). In the summary trial reports on Eli Lilly's website, almost all deaths were noted, but all suicidal ideation events were missing, and the information on the remaining outcomes was incomplete. Because of the shortcomings identified and having only partial access to appendices with no access to case report forms, the harms could not be estimated accurately. In adults there was no significant increase in all four outcomes, but in children and adolescents the risk of suicidality and aggression doubled. To elucidate the harms reliably, access to anonymised individual patient data is needed. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Primary care physician beliefs about insulin initiation in patients with type 2 diabetes

PubMed Central

Hayes, R P; Fitzgerald, J T; Jacober, S J

2008-01-01

Background Insulin is the most effective drug available to achieve glycaemic goals in patients with type 2 diabetes. Yet, there is reluctance among physicians, specifically primary care physicians (PCPs) in the USA, to initiate insulin therapy in these patients. Aims To describe PCPs’ attitudes about the initiation of insulin in patients with type 2 diabetes and identify areas in which there is a clear lack of consensus. Methods Primary care physicians practicing in the USA, seeing 10 or more patients with type 2 diabetes per week, and having > 3 years of clinical practice were surveyed via an internet site. The survey was developed through literature review, qualitative study and expert panel. Results Primary care physicians (n = 505, mean age = 46 years, 81% male, 62% with > 10 years practice; 52% internal medicine) showed greatest consensus on attitudes regarding risk/benefits of insulin therapy, positive experiences of patients on insulin and patient fears or concerns about initiating insulin. Clear lack of consensus was seen in attitudes about the metabolic effects of insulin, need for insulin therapy, adequacy of self-monitoring blood glucose, time needed for training and potential for hypoglycaemia in elderly patients. Conclusions The beliefs of some PCPs are inconsistent with their diabetes treatment goals (HbA1c ≤ 7%). Continuing medical education programmes that focus on increasing primary care physician knowledge about the progression of diabetes, the physiological effects of insulin, and tools for successfully initiating insulin in patients with type 2 diabetes are needed. Disclosures Drs Hayes and Jacober are employees and stockholders of Eli Lilly and Company. Dr Fitzgerald is a consultant to Eli Lilly and Company. What's known Insulin is the most effective drug available to achieve glycaemic goals in patients with type 2 diabetes, yet there is reluctance among many physicians to initiate insulin therapy in these patients. Diabetes specialists tend to be more aggressive than primary care physicians (PCPs) with insulin initiation in patients with type 2 diabetes, and US physicians are more disposed to delay insulin than physicians in other countries. What's new This article confirms that US PCPs lack consensus on some beliefs about insulin initiation. Consensus was seen regarding insulin risk/benefits, positive patient experiences of insulin and patient fears about initiating insulin. No consensus was seen regarding insulin's metabolic effects, need for insulin, adequacy of self-monitoring blood glucose, time needed for training and potential for hypoglycaemia in elderly patients. Some PCPs have beliefs inconsistent with their diabetes treatment goals (HbA1c ≤ 7%). PMID:18393965

Out of Lust or Jealousy: The Effects of Mate-Related Motives on Study-Time Allocation to Faces Varying in Attractiveness.

PubMed

Li, Weijian; Zhang, Yuchi; Li, Fengying; Li, Xinyu; Li, Ping; Jia, Xiaoyu; Chen, Haide; Ji, Haojie

2015-01-01

Although a growing number of empirical studies have revealed that activating mate-related motives might exert a specific set of consequences for human cognition and behaviors, such as attention and memory, little is known about whether mate-related motives affect self-regulated learning. The present study examined the effects of mate-related motives (mate-search and mate-guarding) on study-time allocation to faces varying in attractiveness. In two experiments, participants in mate-related priming conditions (Experiment 1: mate-search; Experiment 2: mate-guarding) or control conditions studied 20 female faces (10 highly attractive, 10 less attractive) during a self-paced study task, and then were given a yes/no face recognition task. The finding of Experiment 1 showed that activating a mate-search motive led the male participants to allocate more time to highly attractive female faces (i.e., perceived potential mates) than to less attractive ones. In Experiment 2, female participants in the mate-guarding priming condition spent more time studying highly attractive female faces (i.e., perceived potential rivals) than less attractive ones, compared to participants in the control condition. These findings illustrate the highly specific consequences of mate-related motives on study-time allocation, and highlight the value of exploring human cognition and motivation within evolutionary and self-regulated learning frameworks.

Out of Lust or Jealousy: The Effects of Mate-Related Motives on Study-Time Allocation to Faces Varying in Attractiveness

PubMed Central

Li, Fengying; Li, Xinyu; Li, Ping; Jia, Xiaoyu; Chen, Haide; Ji, Haojie

2015-01-01

Although a growing number of empirical studies have revealed that activating mate-related motives might exert a specific set of consequences for human cognition and behaviors, such as attention and memory, little is known about whether mate-related motives affect self-regulated learning. The present study examined the effects of mate-related motives (mate-search and mate-guarding) on study-time allocation to faces varying in attractiveness. In two experiments, participants in mate-related priming conditions (Experiment 1: mate-search; Experiment 2: mate-guarding) or control conditions studied 20 female faces (10 highly attractive, 10 less attractive) during a self-paced study task, and then were given a yes/no face recognition task. The finding of Experiment 1 showed that activating a mate-search motive led the male participants to allocate more time to highly attractive female faces (i.e., perceived potential mates) than to less attractive ones. In Experiment 2, female participants in the mate-guarding priming condition spent more time studying highly attractive female faces (i.e., perceived potential rivals) than less attractive ones, compared to participants in the control condition. These findings illustrate the highly specific consequences of mate-related motives on study-time allocation, and highlight the value of exploring human cognition and motivation within evolutionary and self-regulated learning frameworks. PMID:26121131

Love, Lust, and the Emotional Context of Concurrent Sexual Partnerships among Young Swazi Adults

PubMed Central

Ruark, Allison; Dlamini, Lunga; Mazibuko, Nonhlanhla; Green, Edward C.; Kennedy, Caitlin; Nunn, Amy; Flanigan, Timothy; Surkan, Pamela J.

2014-01-01

Men and women in Swaziland who are engaged in multiple or concurrent sexual partnerships, or who have sexual partners with concurrent partners, face a very high risk of HIV infection. Ninety-four in-depth interviews were conducted with 28 Swazi men and women (14 of each sex) between the ages of 20 and 39 in order to explore participants’ sexual partnership histories, including motivations for sexual relationships which carried high HIV risk. Concurrency was normative, with most men and women having had at least one concurrent sexual partnership, and all women reporting having had at least one partner who had a concurrent partner. Men distinguished sexual partnerships that were just for sex from those that were considered to be “real relationships”, while women represented the majority of their relationships, even those which included significant financial support, as being based on love. Besides being motivated by love, concurrent sexual partnerships were described as motivated by a lack of sexual satisfaction, a desire for emotional support and/or as a means to exact revenge against a cheating partner. Social and structural factors were also found to play a role in creating an enabling environment for high-risk sexual partnerships, and these factors included social pressure and norms, a lack of social trust, poverty and a desire for material goods, and geographical separation of partners. PMID:25174630

Passionate Perspectives: Global Change Emersion in Southwestern Dust and Waters

NASA Astrophysics Data System (ADS)

Byrne, J. M.; Little, L. J.

2014-12-01

"Tell me, and I'll forget. Show me, and I may remember. But involve me, and I'll understand" (attributed to various philosophers). How many professors have shared 20-30 days traveling, hiking, camping, and Coleman stove cooking with 25-50 young adults? Sixteen times! Way over a year on a field trip…holy sh*t! Tired… but happy. We have offered an extended camping field trip that feature the highlands and deserts of Utah, Arizona, Mexico and California; with side trips to Colorado and New Mexico. Two science and one social science courses focus on global environmental change, water and human development. The discussion will center on the short and long term evolution(s) that have occurred: who, what, where, when and why, and perhaps most important, HOW! These tours are amazing learning experiences that go way beyond any classroom. Many of our students have found the expedition to be life changing - or life awakening. Hopefully we can squeeze the essence into our few minutes of fame :) "Once more I am roaring drunk with the lust of life and adventure and unbearable beauty... Adventure seems to beset me on all quarters without my even searching for it... Though not all my days are as wild as this, each one holds its surprises, and I have seen almost more beauty than I can bear." - Everett Reuss

Prevalence and Cost of Subsequent Fractures Among U.S. Patients with an Incident Fracture.

PubMed

Weaver, Jessica; Sajjan, Shiva; Lewiecki, E Michael; Harris, Steven T; Marvos, Panagiotis

2017-04-01

The prevalence and cost of subsequent fractures among patients with an incident fracture are not well defined. To assess the prevalence of, and costs associated with, subsequent fractures in the year after an incident fracture. This was a retrospective claims database analysis using data from Humana Medicare Advantage claims (Medicare group) and Optum Insight Clinformatics Data Mart commercial claims (commercial group). Patients included in the study had a claim for a qualifying fracture occurring between January 2008 and December 2013 (index fracture), were continuously enrolled in the health plan for ≥ 1 year before and after the index fracture, and were aged ≥ 65 years in the Medicare group or ≥ 50 years in the commercial group at the time of the index fracture. Subsequent fractures were identified by ICD-9-CM codes and were defined as the second fracture occurring ≥ 3 to ≤ 12 months after the index fracture (≥ 6 to ≤ 12 months for fractures at the same site as the index fracture). Rates of subsequent fractures were calculated as the number of patients who had a subsequent fracture divided by the total sample size. After propensity matching of demographic and clinical variables, we determined the total medical and pharmacy costs accrued within 1 year of the index fracture by patients with and without a subsequent fracture. Health care costs were compared between patients with and without a subsequent fracture using McNemar's test. A total of 45,603 patients were included in the Medicare group, and 54,145 patients were included in the commercial group. In the Medicare group, 7,604 (16.7%) patients experienced a subsequent fracture. The proportion of patients with a subsequent fracture was highest among patients with multiple index fractures (26.2%, n = 905), followed by those with hip (25.5%, n = 1,280) and vertebral (20.2%, n = 1,908) index fractures. In the commercial group, 6,256 (11.6%) patients experienced a subsequent fracture. The proportion of patients with a subsequent fracture paralleled those observed in the Medicare group: 24.5% (n = 808) in patients with multiple index fractures, 22.0% (n = 525) in those with hip fracture, and 14.5% (n = 841) in those with vertebral fracture. For vertebral, hip, and nonhip nonvertebral fractures, subsequent fractures were most frequently of the same type as the index fracture. The mean total health care cost (sum of medical and pharmacy costs) in the year following the incident fracture for the Medicare group was $27,844 and differed significantly between patients with and without a subsequent fracture ($34,897 vs. $20,790; P < 0.001). The mean total health care cost in the year following the incident fracture for the commercial group was $29,316 and also differed significantly between patients with and without a subsequent fracture ($39,501 vs. $19,131; P < 0.001). Among patients with an incident fracture, those who experienced a subsequent fracture in the following year had significantly higher health care costs than those who did not. A subsequent fracture is most likely to be of the same type as the initial fracture. This study was funded by Merck & Co. Other than through the employer relationships disclosed here, Merck & Co did not have a role in the study design, data collection, interpretation of the data, in writing of the manuscript, or in the decision to submit the manuscript for publication. Weaver and Marvos are employees of Merck & Co. Sajjan was an employee of Merck & Co. and owned stock in the company at the time of the study. Lewiecki has received consulting and/or speaker honoraria from Merck, AbbVie, AgNovos Healthcare, Alexion Pharmaceuticals, Amgen, Eli Lilly and Company, Radius Health, Shire, and TheraNova. Lewiecki has received research grant support from Merck, Amgen, and Eli Lilly and Company and serves as a board member for the National Osteoporosis Foundation, the International Society for Clinical Densitometry, and the Osteoporosis Foundation of New Mexico. Harris has received consulting honoraria from Merck, Alexion Pharmaceuticals, Amgen, Eli Lilly and Company, Gilead Sciences, Primus Pharmaceuticals, and Radius Health. Study concept and design were contributed by Weave and Sajjan. Lewiecki collected the data, and data interpretation was performed by all the authors. The manuscript was written and revised by Weaver, Lewiecki, and Harris.

Diagnosis and Treatment of Osteoporosis Before and After Fracture: A Side-by-Side Analysis of Commercially Insured and Medicare Advantage Osteoporosis Patients.

PubMed

Weaver, Jessica; Sajjan, Shiva; Lewiecki, E Michael; Harris, Steven T

2017-07-01

Although treatment for osteoporosis is recommended by U.S. clinical guidelines, a lack of diagnosis and treatment is common among patients with osteoporotic fractures. To determine the rates of osteoporosis diagnosis and treatment before and after various types of fractures. This was a retrospective claims analysis using data from the Humana Medicare Advantage claims (Medicare group) and Optum Insight Clinformatics Data Mart commercial claims (Commercial group). Patients included in the study had a claim for a qualifying fracture occurring between January 2008 and December 2013 (the index fracture), were continuously enrolled in the health plan for ≥ 1 year before and after the index fracture, and were aged ≥ 65 years in the Medicare group or ≥ 50 years in the Commercial group at the time of the index fracture. Fragility fractures and osteoporosis diagnoses were identified from ICD-9-CM codes. Treatment for osteoporosis included oral and injectable therapies identified by National Drug Code numbers and Healthcare Common Procedure Coding System codes. Diagnosis and treatment rates were assessed during the 1-year periods before and after the index fracture. All analyses were conducted by fracture type (vertebral, hip, nonhip/nonvertebral [NHNV], and multiple), with stratification by age and sex. No comparisons were made between the Medicare and Commercial groups; rather, McNemar tests were used to compare prefracture versus postfracture diagnosis and treatment rates within each group. For inclusion in the Medicare group, 45,603 patients were identified, and 54,145 patients were identified for the Commercial group. In the prefracture period, the osteoporosis diagnosis rates ranged from 12.0% (NHNV) to 21.5% (vertebral) in the Medicare group and from 5.3% (NHNV) to 12.1% (vertebral) in the Commercial group. In the postfracture period, diagnosis rates significantly increased (P < 0.001)-and nearly doubled-for all fracture types but did not exceed 42.1% (vertebral) in the Medicare group and 27.7% (vertebral) in the Commercial group. Pre-index treatment rates were similarly low, ranging from 9.4% (hip) to 16.6% (vertebral) among Medicare patients, and 7.5% (NHNV) to 14.4% (vertebral) in Commercial patients. Osteoporosis treatment rates improved significantly in the postfracture year, ranging from 12.5% (NHNV) to 26.5% (vertebral) among Medicare patients, and 8.3% (NHNV) to 21.4% (vertebral) in Commercial patients. Larger increases in diagnosis rates and smaller increases in treatment rates were observed in stratified analyses of men and women and of different age groups, with women and older patients having higher overall rates of diagnosis and treatment before and after fracture. In men and women, osteoporosis diagnosis rates were low before the index fracture and improved substantially after the fracture, yet still remained low overall (under 50%). Osteoporosis treatment rates among patients experiencing a fracture were low before the index fracture and improved only minimally afterwards. This study was funded by Merck & Co. Other than through the employer relationship disclosed here, Merck & Co. did not have a role in the study design, data collection, interpretation of the data, in writing of the manuscript, or in the decision to submit the manuscript for publication. Weaver is an employee of Merck & Co. Sajjan was an employee of Merck & Co. and owned stock in the company at the time of the study. Lewiecki has received consulting and/or speaker honoraria from Merck & Co., AbbVie, AgNovos Healthcare, Alexion Pharmaceuticals, Amgen, Eli Lilly and Company, Radius Health, Shire, and TheraNova, along with research grant support from Merck & Co., Amgen, and Eli Lilly and Company, and serves as a board member for the National Osteoporosis Foundation, the International Society for Clinical Densitometry, and the Osteoporosis Foundation of New Mexico. Harris has received consulting honoraria from Merck & Co., Alexion Pharmaceuticals, Amgen, Eli Lilly and Company, Gilead Sciences, Primus Pharmaceuticals, and Radius Health. Study concept and design were contributed by Weaver and Sajjan. Sajjan collected the data, and data interpretation was performed by all the authors. The manuscript was written and revised by Weaver, Lewiecki, and Harris.

Canadian Consensus Conference on Osteoporosis, 2006 Update

PubMed Central

Brown, Jacques P.; Fortier, Michel

2016-01-01

Objective To provide guidelines for the health care provider on the diagnosis and clinical management of postmenopausal osteoporosis. Outcomes Strategies for identifying and evaluating high-risk individuals, the use of bone mineral density (BMD) and bone turnover markers in assessing diagnosis and response to management, and recommendations regarding nutrition, physical activity, and the selection of pharmacologic therapy to prevent and manage osteoporosis. Evidence MEDLINE and the Cochrane database were searched for articles in English on subjects related to osteoporosis diagnosis, prevention, and management from March 2001 to April 2005. The authors critically reviewed the evidence and developed the recommendations according to the Journal of Obstetrics and Gynaecology Canada’s methodology and consensus development process. Values The quality of evidence is rated using the criteria described in the report of the Canadian Task Force on the Periodic Health Examination. Recommendations for practice are ranked according to the method described in this report. Sponsors The development of this consensus guideline was supported by unrestricted educational grants from Berlex Canada Inc., Lilly Canada, Merck Frosst, Novartis, Novogen, Novo Nordisk, Proctor and Gamble, Schering Canada, and Wyeth Canada. PMID:16626523

International investment agreements and public health: neutralizing a threat through treaty drafting

PubMed Central

2014-01-01

Abstract The high profile investment claims filed by Philip Morris challenging Uruguayan and Australian measures that restrict advertising and logos on tobacco packaging awakened the public health community to the existence and potential detrimental impact of international investment agreements (IIAs). More recently, Eli Lilly challenged Canada’s invalidation of a pharmaceutical patent under an IIA. All of the cases claim that the intellectual property rights of the investor were infringed. As a result of these cases, many commentators and activists view IIAs as a threat to public health and have lobbied against their inclusion in ongoing trade negotiations. This article does not argue against IIAs. Instead, it seeks to demonstrate how more sophisticated treaty drafting can neutralize the threat to public health. In this regard, the article seeks to engage members of the public health community as campaigners not against IIAs but as advocates of better treaty drafting to ensure that IIAs do not infringe upon the right of a nation to take non-discriminatory measures for the promotion and protection of the health of their populations. PMID:25110377

Large-eddy simulation of laminar-turbulent breakdown at high speeds with dynamic subgrid-scale modeling

NASA Technical Reports Server (NTRS)

El-Hady, Nabil M.

1993-01-01

The laminar-turbulent breakdown of a boundary-layer flow along a hollow cylinder at Mach 4.5 is investigated with large-eddy simulation. The subgrid scales are modeled dynamically, where the model coefficients are determined from the local resolved field. The behavior of the dynamic-model coefficients is investigated through both an a priori test with direct numerical simulation data for the same case and a complete large-eddy simulation. Both formulations proposed by Germano et al. and Lilly are used for the determination of unique coefficients for the dynamic model and their results are compared and assessed. The behavior and the energy cascade of the subgrid-scale field structure are investigated at various stages of the transition process. The investigations are able to duplicate a high-speed transition phenomenon observed in experiments and explained only recently by the direct numerical simulations of Pruett and Zang, which is the appearance of 'rope-like' waves. The nonlinear evolution and breakdown of the laminar boundary layer and the structure of the flow field during the transition process were also investigated.

The role of chalcones in suppression of NF-κB-mediated inflammation and cancer.

PubMed

Yadav, Vivek R; Prasad, Sahdeo; Sung, Bokyung; Aggarwal, Bharat B

2011-03-01

Although consumption of fruits, vegetables, spices, cereals and pulses has been associated with lower incidence of cancer and other chronic diseases, how these dietary agents and their active ingredients minimize these diseases, is not fully understood. Whether it is oranges, kawa, hops, water-lilly, locorice, wax apple or mulberry, they are all connected by a group of aromatic ketones, called chalcones (1,3-diaryl-2-propen-1-ones). Some of the most significant chalcones identified from these plants include flavokawin, butein, xanthoangelol, 4-hydroxyderricin, cardamonin, 2',4'-dihydroxychalcone, isoliquiritigenin, isosalipurposide, and naringenin chalcone. These chalcones have been linked with immunomodulation, antibacterial, antifungal, antiviral, anti-inflammatory, antioxidant, anticancer, and antidiabetic activities. The current review, however, deals with the role of various chalcones in inflammation that controls both the immune system and tumorigenesis. Inflammatory pathways have been shown to mediate the survival, proliferation, invasion, angiogenesis and metastasis of tumors. How these chalcones modulate inflammatory pathways, tumorigenesis and immune system is the focus of this review. Copyright © 2010 Elsevier B.V. All rights reserved.

International investment agreements and public health: neutralizing a threat through treaty drafting.

PubMed

Mercurio, Bryan

2014-07-01

The high profile investment claims filed by Philip Morris challenging Uruguayan and Australian measures that restrict advertising and logos on tobacco packaging awakened the public health community to the existence and potential detrimental impact of international investment agreements (IIAs). More recently, Eli Lilly challenged Canada's invalidation of a pharmaceutical patent under an IIA. All of the cases claim that the intellectual property rights of the investor were infringed. As a result of these cases, many commentators and activists view IIAs as a threat to public health and have lobbied against their inclusion in ongoing trade negotiations. This article does not argue against IIAs. Instead, it seeks to demonstrate how more sophisticated treaty drafting can neutralize the threat to public health. In this regard, the article seeks to engage members of the public health community as campaigners not against IIAs but as advocates of better treaty drafting to ensure that IIAs do not infringe upon the right of a nation to take non-discriminatory measures for the promotion and protection of the health of their populations.

The Order of the Dolphin: Origins of SETI

NASA Astrophysics Data System (ADS)

Temming, Maria; Crider, Anthony

2016-01-01

In 1961, the National Academy of Sciences organized a meeting on the search for extraterrestrial intelligence (SETI) at the National Radio Astronomy Observatory in Green Bank, West Virginia. The ten scientists who attended, including future SETI icons such as Frank Drake and Carl Sagan, represented a variety of scientific fields. At the conclusion of the meeting, the attendees adopted the moniker "The Order of the Dolphin," in honor of participant John Lilly's work on interspecies communication. Since this seminal meeting, researchers in each of the attendees' fields have contributed in some way to the search for intelligent life. This study investigates the circumstances that led to each attendee's invitation to Green Bank and explores SETI as the legacy of this meeting. We will focus in this talk on the SETI connections of two attendees, astronomer Otto Struve and physicist Philip Morrison, both in regards to their personal contributions to SETI and the influence of their work on subsequent SETI research. Specifically, we will examine proposals by Otto Struve for exoplanet discovery methods, and Philip Morrison for radio searches that laid the groundwork for modern SETI.

Novel Phenotypic Outcomes Identified for a Public Collection of Approved Drugs from a Publicly Accessible Panel of Assays

PubMed Central

Oliver, Sarah; Willard, Francis S.; Heidler, Steven; Peery, Robert B.; Oler, Jennifer; Chu, Shaoyou; Southall, Noel; Dexheimer, Thomas S.; Smallwood, Jeffrey; Huang, Ruili; Guha, Rajarshi; Jadhav, Ajit; Cox, Karen; Austin, Christopher P.; Simeonov, Anton; Sittampalam, G. Sitta; Husain, Saba; Franklin, Natalie; Wild, David J.; Yang, Jeremy J.; Sutherland, Jeffrey J.; Thomas, Craig J.

2015-01-01

Phenotypic assays have a proven track record for generating leads that become first-in-class therapies. Whole cell assays that inform on a phenotype or mechanism also possess great potential in drug repositioning studies by illuminating new activities for the existing pharmacopeia. The National Center for Advancing Translational Sciences (NCATS) pharmaceutical collection (NPC) is the largest reported collection of approved small molecule therapeutics that is available for screening in a high-throughput setting. Via a wide-ranging collaborative effort, this library was analyzed in the Open Innovation Drug Discovery (OIDD) phenotypic assay modules publicly offered by Lilly. The results of these tests are publically available online at www.ncats.nih.gov/expertise/preclinical/pd2 and via the PubChem Database (https://pubchem.ncbi.nlm.nih.gov/) (AID 1117321). Phenotypic outcomes for numerous drugs were confirmed, including sulfonylureas as insulin secretagogues and the anti-angiogenesis actions of multikinase inhibitors sorafenib, axitinib and pazopanib. Several novel outcomes were also noted including the Wnt potentiating activities of rotenone and the antifolate class of drugs, and the anti-angiogenic activity of cetaben. PMID:26177200

Novel Phenotypic Outcomes Identified for a Public Collection of Approved Drugs from a Publicly Accessible Panel of Assays.

PubMed

Lee, Jonathan A; Shinn, Paul; Jaken, Susan; Oliver, Sarah; Willard, Francis S; Heidler, Steven; Peery, Robert B; Oler, Jennifer; Chu, Shaoyou; Southall, Noel; Dexheimer, Thomas S; Smallwood, Jeffrey; Huang, Ruili; Guha, Rajarshi; Jadhav, Ajit; Cox, Karen; Austin, Christopher P; Simeonov, Anton; Sittampalam, G Sitta; Husain, Saba; Franklin, Natalie; Wild, David J; Yang, Jeremy J; Sutherland, Jeffrey J; Thomas, Craig J

2015-01-01

Phenotypic assays have a proven track record for generating leads that become first-in-class therapies. Whole cell assays that inform on a phenotype or mechanism also possess great potential in drug repositioning studies by illuminating new activities for the existing pharmacopeia. The National Center for Advancing Translational Sciences (NCATS) pharmaceutical collection (NPC) is the largest reported collection of approved small molecule therapeutics that is available for screening in a high-throughput setting. Via a wide-ranging collaborative effort, this library was analyzed in the Open Innovation Drug Discovery (OIDD) phenotypic assay modules publicly offered by Lilly. The results of these tests are publically available online at www.ncats.nih.gov/expertise/preclinical/pd2 and via the PubChem Database (https://pubchem.ncbi.nlm.nih.gov/) (AID 1117321). Phenotypic outcomes for numerous drugs were confirmed, including sulfonylureas as insulin secretagogues and the anti-angiogenesis actions of multikinase inhibitors sorafenib, axitinib and pazopanib. Several novel outcomes were also noted including the Wnt potentiating activities of rotenone and the antifolate class of drugs, and the anti-angiogenic activity of cetaben.

Conformational Dynamics of Insulin

PubMed Central

Hua, Qing-Xin; Jia, Wenhua; Weiss, Michael A.

2011-01-01

We have exploited a prandial insulin analog to elucidate the underlying structure and dynamics of insulin as a monomer in solution. A model was provided by insulin lispro (the active component of Humalog®; Eli Lilly and Co.). Whereas NMR-based modeling recapitulated structural relationships of insulin crystals (T-state protomers), dynamic anomalies were revealed by amide-proton exchange kinetics in D2O. Surprisingly, the majority of hydrogen bonds observed in crystal structures are only transiently maintained in solution, including key T-state-specific inter-chain contacts. Long-lived hydrogen bonds (as defined by global exchange kinetics) exist only at a subset of four α-helical sites (two per chain) flanking an internal disulfide bridge (cystine A20–B19); these sites map within the proposed folding nucleus of proinsulin. The anomalous flexibility of insulin otherwise spans its active surface and may facilitate receptor binding. Because conformational fluctuations promote the degradation of pharmaceutical formulations, we envisage that “dynamic re-engineering” of insulin may enable design of ultra-stable formulations for humanitarian use in the developing world. PMID:22649374

Low coverage sequencing of three echinoderm genomes: the brittle star Ophionereis fasciata, the sea star Patiriella regularis, and the sea cucumber Australostichopus mollis.

PubMed

Long, Kyle A; Nossa, Carlos W; Sewell, Mary A; Putnam, Nicholas H; Ryan, Joseph F

2016-01-01

There are five major extant groups of Echinodermata: Crinoidea (feather stars and sea lillies), Ophiuroidea (brittle stars and basket stars), Asteroidea (sea stars), Echinoidea (sea urchins, sea biscuits, and sand dollars), and Holothuroidea (sea cucumbers). These animals are known for their pentaradial symmetry as adults, unique water vascular system, mutable collagenous tissues, and endoskeletons of high magnesium calcite. To our knowledge, the only echinoderm species with a genome sequence available to date is Strongylocentrotus pupuratus (Echinoidea). The availability of additional echinoderm genome sequences is crucial for understanding the biology of these animals. Here we present assembled draft genomes of the brittle star Ophionereis fasciata, the sea star Patiriella regularis, and the sea cucumber Australostichopus mollis from Illumina sequence data with coverages of 12.5x, 22.5x, and 21.4x, respectively. These data provide a resource for mining gene superfamilies, identifying non-coding RNAs, confirming gene losses, and designing experimental constructs. They will be important comparative resources for future genomic studies in echinoderms.

Beyond Sexual Orientation: Integrating Gender/Sex and Diverse Sexualities via Sexual Configurations Theory.

PubMed

van Anders, Sari M

2015-07-01

Sexual orientation typically describes people's sexual attractions or desires based on their sex relative to that of a target. Despite its utility, it has been critiqued in part because it fails to account for non-biological gender-related factors, partnered sexualities unrelated to gender or sex, or potential divergences between love and lust. In this article, I propose Sexual Configurations Theory (SCT) as a testable, empirically grounded framework for understanding diverse partnered sexualities, separate from solitary sexualities. I focus on and provide models of two parameters of partnered sexuality--gender/sex and partner number. SCT also delineates individual gender/sex. I discuss a sexual diversity lens as a way to study the particularities and generalities of diverse sexualities without privileging either. I also discuss how sexual identities, orientations, and statuses that are typically seen as misaligned or aligned are more meaningfully conceptualized as branched or co-incident. I map out some existing identities using SCT and detail its applied implications for health and counseling work. I highlight its importance for sexuality in terms of measurement and social neuroendocrinology, and the ways it may be useful for self-knowledge and feminist and queer empowerment and alliance building. I also make a case that SCT changes existing understandings and conceptualizations of sexuality in constructive and generative ways informed by both biology and culture, and that it is a potential starting point for sexual diversity studies and research.

The Law of Communicable Diseases Act and disclosure to sexual partners among HIV-positive youth

PubMed Central

Christiansen, Monica; Lalos, Ann; Johansson, Eva. E.

2008-01-01

In Sweden, human immunodeficiency virus (HIV) is included among the venereal diseases covered by the Law of Communicable Diseases Act. HIV-positive (HIV+) people are required to inform their sexual partners about their infection and adopt safe sex behaviours. However, it is unclear how the law is perceived. This study explores how HIV+ youth in Sweden perceive the law, handle their sexuality and disclose their HIV diagnosis to sexual partners. Ten HIV+ women and men between 17 and 24 years of age were recruited from three different HIV infection clinics. These participants were interviewed in depth. The interviews were tape-recorded, transcribed verbatim and analysed according to a grounded theory approach. The core category—cultured to take responsibility—illuminates the informants’ double-edged experiences regarding the law and how they handle disclosure to sexual partners. The legislation implies both support and burden for these HIV+ youth; they feel that they have a great deal of responsibility, sometimes more than they can handle. ‘Switch off lust’, ‘balancing lust, fear and obedience’ and ‘switch off the disease’ are strategies that describe how the informants manage sexuality and disclosure. Young HIV+ people have a difficult time informing partners of their HIV diagnosis and discussing safe sex strategies. These are challenges that health care providers need to take seriously. HIV+ youth need better communication strategies to negotiate safer sex. Staff with extended education on sexuality should be a part of HIV health care. PMID:22639678

The Psycho-Neurology of Cross-Species Affective/Social Neuroscience: Understanding Animal Affective States as a Guide to Development of Novel Psychiatric Treatments.

PubMed

Panksepp, Jaak

During the past half century of research with preclinical animal models, affective neuroscience has helped identify and illuminate the functional neuroanatomies and neurochemistries of seven primary process, i.e., genetically provided emotional systems of mammalian brains. All are subcortically localized, allowing animal models to guide the needed behavioral and neuroscientific analyses at levels of detail that cannot be achieved through human research, including modern brain imaging. They consist of the following neuronal processes: SEEKING/Enthusiasm, RAGE/Anger, FEAR/Anxiety, sexual LUST/Passion, maternal CARE/Nurturance, separation-distress PANIC/Grief and PLAY/Social Joy. Several of these systems figure heavily in social bonding. I will focus here especially on the genesis of depression. Its genesis is significantly influenced by (i) sustained overactivity of the separation-distress PANIC system reflecting severed social bonds and the excessive "psychological pain" of loneliness that can, if sustained, lead to a downward cascade known as psychological despair, and (ii) the despair phase that follows the acute PANIC response, which is characterized by abnormally low activity of the SEEKING, the so-called brain reward networks, leading to amotivational states that characterize depression. Depressive affect is promoted by such brain affective mechanisms of social attachments and social loss as well as diminished arousability of the SEEKING system, leading to chronic dysphoria. To understand why depression feels so bad, we must understand the neural mechanisms that mediate such social feelings.

Circulation of core collection monographs in an academic medical library.

PubMed

Schmidt, C M; Eckerman, N L

2001-04-01

Academic medical librarians responsible for monograph acquisition face a challenging task. From the plethora of medical monographs published each year, academic medical librarians must select those most useful to their patrons. Unfortunately, none of the selection tools available to medical librarians are specifically intended to assist academic librarians with medical monograph selection. The few short core collection lists that are available are intended for use in the small hospital or internal medicine department library. As these are the only selection tools available, however, many academic medical librarians spend considerable time reviewing these collection lists and place heavy emphasis on the acquisition of listed books. The study reported here was initiated to determine whether the circulation of listed books in an academic library justified the emphasis placed on the acquisition of these books. Circulation statistics for "listed" and "nonlisted" books in the hematology (WH) section of Indiana University School of Medicine's Ruth Lilly Medical Library were studied. The average circulation figures for listed books were nearly two times as high as the corresponding figures for the WH books in general. These data support the policies of those academic medical libraries that place a high priority on collection of listed books.

Testing the social competition hypothesis of depression using a simple economic game.

PubMed

Kupferberg, Aleksandra; Hager, Oliver M; Fischbacher, Urs; Brändle, Laura S; Haynes, Melanie; Hasler, Gregor

2016-03-01

Price's social competition hypothesis interprets the depressive state as an unconscious, involuntary losing strategy, which enables individuals to yield and accept defeat in competitive situations. We investigated whether patients who suffer from major depressive disorder (MDD) would avoid competition more often than either patients suffering from borderline personality disorder (BPD) or healthy controls. In a simple paper-folding task healthy participants and patiens with MDD and BPD were matched with two opponents, one with an unknown diagnosis and one who shared their clinical diagnosis, and they had to choose either a competitive or cooperative payment scheme for task completion. When playing against an unknown opponent, but not the opponent with the same diagnosis, the patients with depression chose the competitive payment scheme statistically less often than healthy controls and patients diagnosed with BPD. The competition avoidance against the unknown opponent is consistent with Price's social competition hypothesis. G.H. received research support, consulting fees and speaker honoraria from Lundbeck, AstraZeneca, Servier, Eli Lilly, Roche and Novartis. © The Royal College of Psychiatrists 2016. This is an open access article distributed under the terms of the Creative Commons Non-Commercial, No Derivatives (CC BY-NC-ND) licence.

VizieR Online Data Catalog: hCOSMOS: Hectospec survey of galaxies in COSMOS (Damjanov+, 2018)

NASA Astrophysics Data System (ADS)

Damjanov, I.; Zahid, H. J.; Geller, M. J.; Fabricant, D. G.; Hwang, Ho S.

2018-03-01

We target galaxies with r-band magnitudes 17.77

Microdeformation in Vredefort rocks; evidence for shock metamorphism

NASA Technical Reports Server (NTRS)

Reimold, W. U.; Andreoli, M. A. G.; Hart, R. J.

1988-01-01

Planar microdeformations in quartz from basement or collar rocks of the Vredefort Dome have been cited for years as the main microtextural evidence for shock metamorphism in this structure. In addition, Schreyer describes feldspar recrystallization in rocks from the center of the Dome as the result of transformation of diaplectic glass, and Lilly reported the sighting of mosaicism in quartz. These textural observations are widely believed to indicate either an impact or an internally produced shock origin for the Vredefort Dome. Two types of (mostly sub) planar microdeformations are displayed in quartz grains from Vredefort rocks: (1) fluid inclusion trails, and (2) straight optical discontinuities that sometimes resemble lamellae. Both types occur as single features or as single or multiple sets in quartz grains. Besides qualitative descriptions of cleavage and recrystallization in feldspar and kinkbands in mica, no further microtextural evidence for shock metamorphism at Vredefort has been reported to date. Some 150 thin sections of Vredefort basement rocks were re-examined for potential shock and other deformation effects in all rock-forming minerals. This included petrographic study of two drill cores from the immediate vicinity of the center of the Dome. Observations recorded throughout the granitic core are given along with conclusions.

Indiana Wesleyan University SPS Physics Outreach to Rural Middle School and High School Students

NASA Astrophysics Data System (ADS)

Ostrander, Joshua; Rose, Heath; Burchell, Robert; Ramos, Roberto

2013-03-01

The Society of Physics Students chapter at Indiana Wesleyan University is unusual in that it has no physics major, only physics minors. Yet while just over a year old, IWU-SPS has been active in performing physics outreach to middle school and high school students, and the rural community of Grant County. Our year-old SPS chapter consists of majors from Chemistry, Nursing, Biology, Exercise Science, Computer Science, Psychology, Pastoral Studies, and Science Education, who share a common interest in physics and service to the community. IWU currently has a physics minor and is currently working to build a physics major program. Despite the intrinsic challenges, our multi-disciplinary group has been successful at using physics demonstration equipment and hands-on activities and their universal appeal to raise the interest in physics in Grant County. We report our experience, challenges, and successes with physics outreach. We describe in detail our two-pronged approach: raising the level of physics appreciation among the IWU student community and among pre-college students in a rural community of Indiana. Acknowledgements: We acknowledge the support of the Society of Physics Students through a Marsh White Outreach Award and a Blake Lilly Prize.

Circulation of core collection monographs in an academic medical library

PubMed Central

Schmidt, Cynthia M.; Eckerman, Nancy L.

2001-01-01

Academic medical librarians responsible for monograph acquisition face a challenging task. From the plethora of medical monographs published each year, academic medical librarians must select those most useful to their patrons. Unfortunately, none of the selection tools available to medical librarians are specifically intended to assist academic librarians with medical monograph selection. The few short core collection lists that are available are intended for use in the small hospital or internal medicine department library. As these are the only selection tools available, however, many academic medical librarians spend considerable time reviewing these collection lists and place heavy emphasis on the acquisition of listed books. The study reported here was initiated to determine whether the circulation of listed books in an academic library justified the emphasis placed on the acquisition of these books. Circulation statistics for “listed” and “nonlisted” books in the hematology (WH) section of Indiana University School of Medicine's Ruth Lilly Medical Library were studied. The average circulation figures for listed books were nearly two times as high as the corresponding figures for the WH books in general. These data support the policies of those academic medical libraries that place a high priority on collection of listed books. PMID:11337947

Explaining errors in children's questions.

PubMed

Rowland, Caroline F

2007-07-01

The ability to explain the occurrence of errors in children's speech is an essential component of successful theories of language acquisition. The present study tested some generativist and constructivist predictions about error on the questions produced by ten English-learning children between 2 and 5 years of age. The analyses demonstrated that, as predicted by some generativist theories [e.g. Santelmann, L., Berk, S., Austin, J., Somashekar, S. & Lust. B. (2002). Continuity and development in the acquisition of inversion in yes/no questions: dissociating movement and inflection, Journal of Child Language, 29, 813-842], questions with auxiliary DO attracted higher error rates than those with modal auxiliaries. However, in wh-questions, questions with modals and DO attracted equally high error rates, and these findings could not be explained in terms of problems forming questions with why or negated auxiliaries. It was concluded that the data might be better explained in terms of a constructivist account that suggests that entrenched item-based constructions may be protected from error in children's speech, and that errors occur when children resort to other operations to produce questions [e.g. Dabrowska, E. (2000). From formula to schema: the acquisition of English questions. Cognitive Liguistics, 11, 83-102; Rowland, C. F. & Pine, J. M. (2000). Subject-auxiliary inversion errors and wh-question acquisition: What children do know? Journal of Child Language, 27, 157-181; Tomasello, M. (2003). Constructing a language: A usage-based theory of language acquisition. Cambridge, MA: Harvard University Press]. However, further work on constructivist theory development is required to allow researchers to make predictions about the nature of these operations.

Clinical Holistic Medicine: Holistic Sexology and Acupressure Through the Vagina (Hippocratic Pelvic Massage)

PubMed Central

Ventegodt, Søren; Clausen, Birgitte; Omar, Hatim A.; Merrick, Joav

2006-01-01

Many gynecological and sexological problems (like urine incontinence, chronic pelvic pains, vulvodynia, and lack of lust, excitement, and orgasm) are resistant to standard medical treatment. In our work at the Research Clinic for Holistic Medicine in Copenhagen, we have found that vaginal acupressure, or Hippocratic pelvic massage, can help some of these problems. Technically, it is a very simple procedure as it corresponds to the explorative phase of the standard pelvic examination, supplemented with the patient's report on the feelings it provokes and the processing and integration of these feelings. Sometimes it can be very difficult to control the emotions released by the technique, i.e., regression to earlier traumas from childhood sexual abuse. This review discusses the theory behind vaginal acupressure, ethical aspects, and presentation of a case story. This procedure helped the patient to become present in her pelvis and to integrate old traumas with painful emotions. Holistic gynecology and sexology can help the patient to identify and let go of negative feelings, beliefs, and attitudes related to sex, gender, sexual organs, body, and soul at large. Shame, guilt, helplessness, fear, disgust, anxiety, anger, hatred, and other strong feelings are almost always an important part of a sexual or functional problem as these feelings are “held” by the tissue of the pelvis and sexual organs. Acupressure through the vagina/pelvic massage must be done with great care by an experienced physician, with a third person present, after obtaining consent and the necessary trust of the patient. It must be followed by conversational therapy and further holistic existential processing. PMID:17370003

Common plant toxicology: A comparison of national and Southwest Ohio data trends on plant poisonings in the 21st century

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

Petersen, Dan D., E-mail: petersen.dan@epa.gov

Data from the American Association of Poison Control Centers (AAPCC) and the Cincinnati-based Drug and Poison Information Center (DPIC) were analyzed to determine the incidence and trends of human plant poisonings since the year 2000. Approximately 3.4% of the approximately 4.3 million annual calls to the AAPCC centers involved plants, with a higher fraction (4.5%) for pediatric exposures. Nearly 70% of plant exposures occurred in children under six. Only 8% of cases required treatment in a health-care facility, and only 0.1% (in 2008) were considered severe outcomes. The most prominent groups of plants involved in exposures are those containing oxalates,more » and the most common symptom is gastroenteritis. The top 12 identified plants (in descending order) nationally were Spathiphyllum species (peace lilly), Philodendron species (philodendron), Euphorbia pulcherrima (poinssettia), Ilex species (holly), Phytolacca americana (pokeweed), Toxicodendron radicans (poison ivy), Capsicum (pepper), Ficus (rubber tree, weeping fig), Crassula argentea (jade plant), Diffenbachia (dumb cane), Epipremnum areum (pothos) and Schlumbergera bridesii (Christmas cactus). Broad overlaps between the DPIC and the AAPCC incidence data were noted, with essentially the same plant species in each dataset. The nature of the various toxins, the symptomatology and potential treatments are discussed for the highest ranking plant species.« less

Design and Development of a Technology Platform for DNA-Encoded Library Production and Affinity Selection.

PubMed

Castañón, Jesús; Román, José Pablo; Jessop, Theodore C; de Blas, Jesús; Haro, Rubén

2018-06-01

DNA-encoded libraries (DELs) have emerged as an efficient and cost-effective drug discovery tool for the exploration and screening of very large chemical space using small-molecule collections of unprecedented size. Herein, we report an integrated automation and informatics system designed to enhance the quality, efficiency, and throughput of the production and affinity selection of these libraries. The platform is governed by software developed according to a database-centric architecture to ensure data consistency, integrity, and availability. Through its versatile protocol management functionalities, this application captures the wide diversity of experimental processes involved with DEL technology, keeps track of working protocols in the database, and uses them to command robotic liquid handlers for the synthesis of libraries. This approach provides full traceability of building-blocks and DNA tags in each split-and-pool cycle. Affinity selection experiments and high-throughput sequencing reads are also captured in the database, and the results are automatically deconvoluted and visualized in customizable representations. Researchers can compare results of different experiments and use machine learning methods to discover patterns in data. As of this writing, the platform has been validated through the generation and affinity selection of various libraries, and it has become the cornerstone of the DEL production effort at Lilly.

The effect of federal and state off-label marketing investigations on drug prescribing: The case of olanzapine.

PubMed

Wang, Bo; Studdert, David M; Sarpatwari, Ameet; Franklin, Jessica M; Landon, Joan; Kesselheim, Aaron S

2017-01-01

In the past decade, the federal government has frequently investigated and prosecuted pharmaceutical manufacturers for illegal promotion of drugs for indications not approved by the Food and Drug Administration (FDA) ("off-label" uses). State governments can choose to coordinate with the federal investigation, or pursue their own independent state investigations. One of the largest-ever off-label prosecutions relates to the atypical antipsychotic drug olanzapine (Zyprexa). In a series of settlements between 2008 and 2010, Eli Lilly paid $1.4 billion to the federal government and over $290 million to state governments. We examined the effect of these settlements on off-label prescribing of this medication, taking advantage of geographical differences in states' involvement in the investigations and the timing of the settlements. However, we did not find a reduction in off-label prescribing; rather, there were no prescribing changes among states that joined the federal investigation, those that pursued independent state investigations, and states that pursued no investigations at all. Since the settlements of state investigations of off-label prescribing do not appear to significantly impact prescribing rates, policymakers should consider alternate ways of reducing the prevalence of non-evidence-based off-label use to complement their ongoing investigations.

Open Innovation Drug Discovery (OIDD): a potential path to novel therapeutic chemical space.

PubMed

Alvim-Gaston, Maria; Grese, Timothy; Mahoui, Abdelaziz; Palkowitz, Alan D; Pineiro-Nunez, Marta; Watson, Ian

2014-01-01

The continued development of computational and synthetic methods has enabled the enumeration or preparation of a nearly endless universe of chemical structures. Nevertheless, the ability of this chemical universe to deliver small molecules that can both modulate biological targets and have drug-like physicochemical properties continues to be a topic of interest to the pharmaceutical industry and academic researchers alike. The chemical space described by public, commercial, in-house and virtual compound collections has been interrogated by multiple approaches including biochemical, cellular and virtual screening, diversity analysis, and in-silico profiling. However, current drugs and known chemical probes derived from these efforts are contained within a remarkably small volume of the predicted chemical space. Access to more diverse classes of chemical scaffolds that maintain the properties relevant for drug discovery is certainly needed to meet the increasing demands for pharmaceutical innovation. The Lilly Open Innovation Drug Discovery platform (OIDD) was designed to tackle barriers to innovation through the identification of novel molecules active in relevant disease biology models. In this article we will discuss several computational approaches towards describing novel, biologically active, drug-like chemical space and illustrate how the OIDD program may facilitate access to previously untapped molecules that may aid in the search for innovative pharmaceuticals.

Characterization of Petroleum Residue in the Entrada Sandstone, Colorado National Monument

USGS Publications Warehouse

Lillis, Paul G.; King, J. David

2007-01-01

Introduction As part of the U.S. Geological Survey's (USGS) petroleum resource assessment of the Uinta-Piceance Province, Colorado and Utah, in 2000 (USGS Uinta-Piceance Assessment Team, 2003), some 170 oils, oil stains, and oil seeps were geochemically characterized and divided into genetic types (Lillis and others, 2003). Recognized oil types include Minturn, Phosphoria, Grassy Trail Creek, Mancos, Mesaverde, and Green River. Subsequent to that study, the existence and general locality of petroleum residue in the Middle Jurassic Entrada Sandstone in Colorado National Monument (CNM) was brought to the attention of the authors (Scott and others, 2001). Because the analysis of such non-commercial petroleum deposits commonly yields valuable regional resource-trend information, we collected and characterized the reported CNM petroleum residue and compared the results with identified oil types in the Uinta-Piceance Province. Three samples of Entrada Sandstone with petroleum residue were collected near Little Park Road along the south edge of the CNM in sec.20, T.12S., R.101W. The approximate extent of the petroleum staining was determined by field testing with solvent, and the stains appear to be restricted to the upper part of the 'board beds' unit (informal name, Scott and others, 2001) of the Entrada Sandstone between the two fault traces of the Glade Park fault.

Nonsteroidal antagonists of the mineralocorticoid receptor.

PubMed

Kolkhof, Peter; Nowack, Christina; Eitner, Frank

2015-09-01

The broad clinical use of steroidal mineralocorticoid receptor antagonists (MRAs) is limited by the potential risk of inducing hyperkalemia when given on top of renin-angiotensin system blockade. Drug discovery campaigns have been launched aiming for the identification of nonsteroidal MRAs with an improved safety profile. This review analyses the evidence for the potential of improved safety profiles of nonsteroidal MRAs and the current landscape of clinical trials with nonsteroidal MRAs. At least three novel nonsteroidal MRAs have reportedly demonstrated an improved therapeutic index (i.e. less risk for hyperkalemia) in comparison to steroidal antagonists in preclinical models. Five pharmaceutical companies have nonsteroidal MRAs in clinical development with a clear focus on the treatment of chronic kidney diseases. No clinical data have been published so far for MT-3995 (Mitsubishi), SC-3150 (Daiichi-Sankyo), LY2623091 (Eli Lilly) and PF-03882845 (Pfizer). In contrast, data from two clinical phase II trials are available for finerenone (Bayer) which demonstrated safety and efficacy in patients with heart failure and additional chronic kidney diseases, and significantly reduced albuminuria in patients with diabetic nephropathy. Neither hyperkalemia nor reductions in kidney function were limiting factors to its use. Novel, nonsteroidal MRAs are currently tested in clinical trials. Based on preclinical and first clinical data, these nonsteroidal MRAs might overcome the limitations of today's steroidal antagonists.

The influence of misrepresenting the nocturnal boundary layer on idealized daytime convection in large-eddy simulation

NASA Astrophysics Data System (ADS)

van Stratum, Bart J. H.; Stevens, Bjorn

2015-06-01

The influence of poorly resolving mixing processes in the nocturnal boundary layer (NBL) on the development of the convective boundary layer the following day is studied using large-eddy simulation (LES). Guided by measurement data from meteorological sites in Cabauw (Netherlands) and Hamburg (Germany), the typical summertime NBL conditions for Western Europe are characterized, and used to design idealized (absence of moisture and large-scale forcings) numerical experiments of the diel cycle. Using the UCLA-LES code with a traditional Smagorinsky-Lilly subgrid model and a simplified land-surface scheme, a sensitivity study to grid spacing is performed. At horizontal grid spacings ranging from 3.125 m in which we are capable of resolving most turbulence in the cases of interest to grid a spacing of 100 m which is clearly insufficient to resolve the NBL, the ability of LES to represent the NBL and the influence of NBL biases on the subsequent daytime development of the convective boundary layer are examined. Although the low-resolution experiments produce substantial biases in the NBL, the influence on daytime convection is shown to be small, with biases in the afternoon boundary layer depth and temperature of approximately 100 m and 0.5 K, which partially cancel each other in terms of the mixed-layer top relative humidity.

Seasonal and annual variation in the diet of Atlantic cod (Gadus morhua) in relation to the abundance of capelin (Mallotus villosus) off eastern Newfoundland, Canada

USGS Publications Warehouse

Methven, David A.; Piatt, John F.

1989-01-01

The importance of capelin as prey for cod has long been known (Thompson, 1943; and see Lilly (1987) for a review); however, no studies have been conducted on how the highly dynamic seasonal and yearly variations in capelin abundance affect cod diet. We studied the occurrence of capelin in cod stomachs in relation to the relative abundance of capelin at Witless Bay, Newfoundland (47°15’N 52°46’W), during June, July and August, 1982-1984. The mean number of capelin per stomach and the per cent occurrence of stomachs containing capelin were determined for each collection of stomachs. A total of 680 stomachs were examined. Cod were sampled from those caught in gillnets by fishermen and averaged 66 cm ± 8 (s.d.) in 1983 and 62 cm ± 8 (s.d.) in 1984. Relative abundance of capelin in the local habitat was determined by conducting hydroacoustic surveys around Gull Island in Witless Bay, the same area where cod were collected for stomach content analysis. Only hydroacoustic surveys conducted within three days of cod stomach collections were analyzed. Further details of hydroacoustic surveys including quantifications of acoustic echograms are described in Piatt (1989).

Antipsychotic metabolic effects: weight gain, diabetes mellitus, and lipid abnormalities.

PubMed

McIntyre, R S; McCann, S M; Kennedy, S H

2001-04-01

To review published and nonpublished literature describing changes in weight, glucose homeostasis, and lipid milieu with antipsychotics. A Medline search was completed using the words weight gain, diabetes mellitus, cholesterol, triglycerides, risperidone, clozapine, olanzapine, quetiapine, ziprasidone, predictors, prolactin, obesity, and conventional antipsychotics. Publications, including original articles, review articles, letters to the editor, abstracts or posters presented at professional meetings in the last 4 years, and references from published articles, were collected. Manufacturers, including Eli Lilly Canada Inc, JanssenOrtho Inc, Pfizer Canada Inc, AstraZeneca Inc, and Novartis Pharmaceuticals, were contacted to retrieve additional medical information. The topic of antipsychotic-induced weight gain is understudied, and there are relatively few well-controlled studies. Weight gain as a side effect has been described with both conventional and atypical antipsychotics. Moreover, some atypical antipsychotics are associated with de novo diabetes mellitus and increased serum triglyceride levels. Predictors of weight gain may be age, baseline body mass index, appetite stimulation, previous antipsychotic exposure, and antipsychotic treatment duration. Significant weight gain is reported with the existing atypical antipsychotics. The weight gain described is highly distressing to patients, may reduce treatment adherence, and may increase the relative risk for diabetes mellitus and hypertriglyceridemia. Physicians employing these agents should routinely monitor weight, fasting blood glucose, and lipid profiles.

Abortion.

PubMed

Savage, A

1979-09-15

I refer for termination anyone who requests it for--pace Mr V Tunkel, (28 July, p 253)--the law is generally regarded as being one of "abortion on demand." I have some misgivings as I do not believe that women in early pregnancy are always in a fit state to make a considered decision, and they cannot in the nature of things be given time. I have, however, become increasingly worried about the morbidity arising from the procedure, and it is interesting that letters on the subject (25 August, pp 495 and 496) should be followed by one reporting rupture of the uterus during prostaglandin-induced abortion--yet another complication to add to those of cervical incompetence, pelvic sepsis, and permanent neurological damage. In so far as these tragedies usually follow late terminations Mr John Corrie's Bill is to be welcomed. A few further points. I am not so cynical as to think that every impregnation is the result of a thoughtless act of male lust. Unlike Professor Peter Huntingford (25 August, p 496), I listen to men as well as women, and many of them are deeply involved emotionally in the pregnancy they have helped to produce. Certainly I think a man should have the right to be consulted if his wife is to undergo a procedure that might damage her health. It is unfair contemptuously to dismiss as "whims" opinions that differ from ones own. These may result from genuine conscientious doubts or inability to cope from overwork and understaffing. Abortion is quite the most expensive form of contraception, and perhaps in these days of financial stringency this should be taken into account. "Bigotry" is defined in my dictionary as "blind zeal." This could be said of those who enthusiastically promote a course of action without regard to circumstances, safety, or cost.

The expression and recognition of emotions in the voice across five nations: A lens model analysis based on acoustic features.

PubMed

Laukka, Petri; Elfenbein, Hillary Anger; Thingujam, Nutankumar S; Rockstuhl, Thomas; Iraki, Frederick K; Chui, Wanda; Althoff, Jean

2016-11-01

This study extends previous work on emotion communication across cultures with a large-scale investigation of the physical expression cues in vocal tone. In doing so, it provides the first direct test of a key proposition of dialect theory, namely that greater accuracy of detecting emotions from one's own cultural group-known as in-group advantage-results from a match between culturally specific schemas in emotional expression style and culturally specific schemas in emotion recognition. Study 1 used stimuli from 100 professional actors from five English-speaking nations vocally conveying 11 emotional states (anger, contempt, fear, happiness, interest, lust, neutral, pride, relief, sadness, and shame) using standard-content sentences. Detailed acoustic analyses showed many similarities across groups, and yet also systematic group differences. This provides evidence for cultural accents in expressive style at the level of acoustic cues. In Study 2, listeners evaluated these expressions in a 5 × 5 design balanced across groups. Cross-cultural accuracy was greater than expected by chance. However, there was also in-group advantage, which varied across emotions. A lens model analysis of fundamental acoustic properties examined patterns in emotional expression and perception within and across groups. Acoustic cues were used relatively similarly across groups both to produce and judge emotions, and yet there were also subtle cultural differences. Speakers appear to have a culturally nuanced schema for enacting vocal tones via acoustic cues, and perceivers have a culturally nuanced schema in judging them. Consistent with dialect theory's prediction, in-group judgments showed a greater match between these schemas used for emotional expression and perception. (PsycINFO Database Record (c) 2016 APA, all rights reserved).

Do conceptualisations of health differ across social strata? A concept mapping study among lay people

PubMed Central

Stronks, Karien; Hoeymans, Nancy; Haverkamp, Beatrijs; den Hertog, Frank R J; van Bon-Martens, Marja J H; Galenkamp, Henrike; Verweij, Marcel; van Oers, Hans A M

2018-01-01

Objectives The legitimacy of policies that aim at tackling socioeconomic inequalities in health can be challenged if they do not reflect the conceptualisations of health that are valued in all strata. Therefore, this study analyses how different socioeconomic groups formulate their own answers regarding: what does health mean to you? Design Concept mapping procedures were performed in three groups that differ in educational level. All procedures followed exactly the same design. Setting Area of the city of Utrecht, the Netherlands. Participants Lay persons with a lower, intermediate and higher educational level (±15/group). Results The concept maps for the three groups consisted of nine, eight and seven clusters each, respectively. Four clusters occurred in all groups: absence of disease/disabilities, health-related behaviours, social life, attitude towards life. The content of some of these differed between groups, for example, behaviours were interpreted as having opportunities to behave healthily in the lower education group, and in terms of their impact on health in the higher education group. Other clusters appeared to be specific for particular groups, such as autonomy (intermediate/higher education group). Finally, ranking ranged from a higher ranking of the positively formulated aspects in the higher education group (eg, lust for life) to that of the negatively formulated aspects in the lower education group (eg, having no chronic disease). Conclusion Our results provide indications to suggest that people in lower socioeconomic groups are more likely to show a conceptualisation of health that refers to (1) the absence of health threats (vs positive aspects), (2) a person within his/her circumstances (vs quality of own body/mind), (3) the value of functional (vs hedonistic) notions and (4) an accepting (vs active) attitude towards life. PMID:29674369

Body language in the brain: constructing meaning from expressive movement.

PubMed

Tipper, Christine M; Signorini, Giulia; Grafton, Scott T

2015-01-01

This fMRI study investigated neural systems that interpret body language-the meaningful emotive expressions conveyed by body movement. Participants watched videos of performers engaged in modern dance or pantomime that conveyed specific themes such as hope, agony, lust, or exhaustion. We tested whether the meaning of an affectively laden performance was decoded in localized brain substrates as a distinct property of action separable from other superficial features, such as choreography, kinematics, performer, and low-level visual stimuli. A repetition suppression (RS) procedure was used to identify brain regions that decoded the meaningful affective state of a performer, as evidenced by decreased activity when emotive themes were repeated in successive performances. Because the theme was the only feature repeated across video clips that were otherwise entirely different, the occurrence of RS identified brain substrates that differentially coded the specific meaning of expressive performances. RS was observed bilaterally, extending anteriorly along middle and superior temporal gyri into temporal pole, medially into insula, rostrally into inferior orbitofrontal cortex, and caudally into hippocampus and amygdala. Behavioral data on a separate task indicated that interpreting themes from modern dance was more difficult than interpreting pantomime; a result that was also reflected in the fMRI data. There was greater RS in left hemisphere, suggesting that the more abstract metaphors used to express themes in dance compared to pantomime posed a greater challenge to brain substrates directly involved in decoding those themes. We propose that the meaning-sensitive temporal-orbitofrontal regions observed here comprise a superordinate functional module of a known hierarchical action observation network (AON), which is critical to the construction of meaning from expressive movement. The findings are discussed with respect to a predictive coding model of action understanding.

I was greedy, too.

PubMed

Coutu, Diane L

2003-02-01

Americans are outraged at the greediness of Wall Street analysts, dot-com entrepreneurs, and, most of all, chief executive officers. How could Tyco's Dennis Kozlowski use company funds to throw his wife a million-dollar birthday bash on an Italian island? How could Enron's Ken Lay sell thousands of shares of his company's once high-flying stock just before it crashed, leaving employees with nothing? Even America's most popular domestic guru, Martha Stewart, is suspected of having her hand in the cookie jar. To some extent, our outrage may be justified, writes HBR senior editor Diane Coutu. And yet, it's easy to forget that just a couple years ago these same people were lauded as heroes. Many Americans wanted nothing more, in fact, than to emulate them, to share in their fortunes. Indeed, we spent an enormous amount of time talking and thinking about double-digit returns, IPOs, day trading, and stock options. It could easily be argued that it was public indulgence in corporate money lust that largely created the mess we're now in. It's time to take a hard look at greed, both in its general form and in its peculiarly American incarnation, says Coutu. If Federal Reserve Board chairman Alan Greenspan was correct in telling Congress that "infectious greed" contaminated U.S. business, then we need to try to understand its causes--and how the average American may have contributed to it. Why did so many of us fall prey to greed? With a deep, almost reflexive trust in the free market, are Americans somehow greedier than other peoples? And as we look at the wreckage from the 1990s, can we be sure it won't happen again?

Disgust versus Lust: Exploring the Interactions of Disgust and Fear with Sexual Arousal in Women.

PubMed

Fleischman, Diana S; Hamilton, Lisa Dawn; Fessler, Daniel M T; Meston, Cindy M

2015-01-01

Sexual arousal is a motivational state that moves humans toward situations that inherently pose a risk of disease transmission. Disgust is an emotion that adaptively moves humans away from such situations. Incongruent is the fact that sexual activity is elementary to human fitness yet involves strong disgust elicitors. Using an experimental paradigm, we investigated how these two states interact. Women (final N=76) were assigned to one of four conditions: rate disgust stimuli then watch a pornographic clip; watch a pornographic clip then rate disgust stimuli; rate fear stimuli then watch a pornographic clip; or watch a pornographic clip then rate fear stimuli. Women's genital sexual arousal was measured with vaginal photoplethysmography and their disgust and fear reactions were measured via self-report. We did not find that baseline disgust propensity predicted sexual arousal in women who were exposed to neutral stimuli before erotic content. In the Erotic-before-Disgust condition we did not find that sexual arousal straightforwardly predicted decreased image disgust ratings. However, we did find some evidence that sexual arousal increased self-reported disgust in women with high trait disgust and sexual arousal decreased self-reported disgust in women with low trait disgust. Women who were exposed to disgusting images before erotic content showed significantly less sexual arousal than women in the control condition or women exposed to fear-inducing images before erotic content. In the Disgust-before-Erotic condition the degree of self-reported disgust was negatively correlated with genital sexual arousal. Hence, in the conflict between the ultimate goals of reproduction and disease avoidance, cues of the presence of pathogens significantly reduce the motivation to engage in mating behaviors that, by their nature, entail a risk of pathogen transmission.

Disgust versus Lust: Exploring the Interactions of Disgust and Fear with Sexual Arousal in Women

PubMed Central

Fleischman, Diana S.; Hamilton, Lisa Dawn; Fessler, Daniel M. T.; Meston, Cindy M.

2015-01-01

Sexual arousal is a motivational state that moves humans toward situations that inherently pose a risk of disease transmission. Disgust is an emotion that adaptively moves humans away from such situations. Incongruent is the fact that sexual activity is elementary to human fitness yet involves strong disgust elicitors. Using an experimental paradigm, we investigated how these two states interact. Women (final N=76) were assigned to one of four conditions: rate disgust stimuli then watch a pornographic clip; watch a pornographic clip then rate disgust stimuli; rate fear stimuli then watch a pornographic clip; or watch a pornographic clip then rate fear stimuli. Women’s genital sexual arousal was measured with vaginal photoplethysmography and their disgust and fear reactions were measured via self-report. We did not find that baseline disgust propensity predicted sexual arousal in women who were exposed to neutral stimuli before erotic content. In the Erotic-before-Disgust condition we did not find that sexual arousal straightforwardly predicted decreased image disgust ratings. However, we did find some evidence that sexual arousal increased self-reported disgust in women with high trait disgust and sexual arousal decreased self-reported disgust in women with low trait disgust. Women who were exposed to disgusting images before erotic content showed significantly less sexual arousal than women in the control condition or women exposed to fear-inducing images before erotic content. In the Disgust-before-Erotic condition the degree of self-reported disgust was negatively correlated with genital sexual arousal. Hence, in the conflict between the ultimate goals of reproduction and disease avoidance, cues of the presence of pathogens significantly reduce the motivation to engage in mating behaviors that, by their nature, entail a risk of pathogen transmission. PMID:26106894

Common plant toxicology: a comparison of national and southwest Ohio data trends on plant poisonings in the 21st century.

PubMed

Petersen, Dan D

2011-07-15

Data from the American Association of Poison Control Centers (AAPCC) and the Cincinnati-based Drug and Poison Information Center (DPIC) were analyzed to determine the incidence and trends of human plant poisonings since the year 2000. Approximately 3.4% of the approximately 4.3 million annual calls to the AAPCC centers involved plants, with a higher fraction (4.5%) for pediatric exposures. Nearly 70% of plant exposures occurred in children under six. Only 8% of cases required treatment in a health-care facility, and only 0.1% (in 2008) were considered severe outcomes. The most prominent groups of plants involved in exposures are those containing oxalates, and the most common symptom is gastroenteritis. The top 12 identified plants (in descending order) nationally were Spathiphyllum species (peace lilly), Philodendron species (philodendron), Euphorbia pulcherrima (poinssettia), Ilex species (holly), Phytolacca americana (pokeweed), Toxicodendron radicans (poison ivy), Capsicum (pepper), Ficus (rubber tree, weeping fig), Crassula argentea (jade plant), Diffenbachia (dumb cane), Epipremnum areum (pothos) and Schlumbergera bridesii (Christmas cactus). Broad overlaps between the DPIC and the AAPCC incidence data were noted, with essentially the same plant species in each dataset. The nature of the various toxins, the symptomatology and potential treatments are discussed for the highest ranking plant species. Copyright © 2011 Elsevier Inc. All rights reserved.

Crustal and Upper Mantle S-velocity Structure From Receiver Functions Analisys Around Terra Nova Bay Base, Antartica

NASA Astrophysics Data System (ADS)

Piana Agostinetti, N.; Amato, A.; Cattaneo, M.; de Gori, P.; di Bona, M.

In the framework of the italian PNRA (Progetto Nazionale di Ricerche in Antartide), we have started to re-analize teleseismic waveforms recorded, using three-components seismometers (equipped with 5 seconds sensors, Lennartz 3D-5s), during five summer campaings, from 1993 to 2000. Seismic stations were deployed around Terra Nova Bay (TNB) italian base, from the sea to reach the interior of the Transantartic Moun- tains (TAM), the most striking example of nocontractional mountain belt. During the last campaingn (1999-2000) seismic stations were deployed deep into Northern Vic- toria Land to reach Rennik and Lillie Glaciers Area and George V coast region, the northest part of TAM. Our main goals were: to compute, using frequency-domanin deconvolution method by Di Bona [1998], Receiver Functions covering all the area around TNB italian antartic base; to map of Moho-depth and intercrustal S-waves ve- locity discontinuity from 1-D velocity model computed using Sambridge's inversion scheme [Sambridge,1999]; to analize new teleseimic waveforms recorded near TNB base: continuos recording, from 1999 to present, permits more accurate modelling S-velocity crustal structure in this critical area situated at the edge of the ipothetic rift [Stern and ten Brik, 1989; Stump and Fitzgerald, 1992; ten Brik et al., 1997]; to present final results from BACKTAM expedition.

Evaluation of oral tilmicosin efficacy against severe cryptosporidiosis in neonatal kids under field conditions.

PubMed

Paraud, C; Pors, I; Chartier, C

2010-05-28

Many compounds have been screened for their potential anti-cryptosporidial activity in ruminants but none of them has been totally efficient in controlling the disease. Macrolide antibiotics have demonstrated some activity against Cryptosporidium spp. in humans. Tilmicosin is a macrolide antibiotic, available in France in an oral form (Pulmotil AC, Lilly France). The preventive efficacy of tilmicosin was evaluated in a goat farm experiencing severe clinical cryptosporidiosis in kids. Twenty-two kids were separated from their dams just after birth and placed in a separated pen. They were divided into 3 groups: an untreated group (10 kids), group 1 (6 kids) receiving tilmicosin at 25mg/kg BW/day and group 2 (6 kids) receiving tilmicosin at 50mg/kg BW/day. Tilmicosin was individually given by oral route from day 2 of age for 10 days. Three times a week, individual faecal samples were performed to assess the oocyst output. Clinical data, i.e. diarrhea and mortality, were recorded. In control kids, the highest prevalence and intensity of excretion were observed between day 6 and day 16 of age and mortality reached 90%. Excretion dynamic and clinical consequences were similar in both treated kid groups. Finally, tilmicosin did not demonstrate any activity against severe kid cryptosporidiosis in field conditions. (c) 2010 Elsevier B.V. All rights reserved.

Evaluation of Cardiac Toxicity Biomarkers in Rats from Different Laboratories

PubMed Central

Kim, Kyuri; Chini, Naseem; Fairchild, David G.; Engle, Steven K.; Reagan, William J.; Summers, Sandra D.; Mirsalis, Jon C.

2016-01-01

There is a great need for improved diagnostic and prognostic accuracy of potential cardiac toxicity in drug development. This study reports the evaluation of several commercially available biomarker kits by three institutions (SRI, Eli Lilly and Pfizer) for the discrimination between myocardial degeneration/necrosis and cardiac hypertrophy as well as the assessment of the inter-laboratory and inter-platform variation in results. Serum concentrations of natriuretic peptides (NT-proANP, NT-proBNP), cardiac and skeletal troponins (cTnI, cTnT, sTnI), myosin light chain 3 (Myl3) and fatty acid binding protein 3 (FABP3) were assessed in rats treated with minoxidil and isoproterenol. Minoxidil caused increased heart-to-body weight ratios and prominent elevations in NT-proANP and NT-proBNP concentrations detected at 24 hr postdose without elevation in troponins, Myl3 or FABP3 and with no abnormal histopathological findings. Isoproterenol caused ventricular leukocyte infiltration, myocyte fibrosis and necrosis with increased concentrations of the natriuretic peptides, cardiac troponins and Myl3. These results reinforce the advantages of a multi-marker strategy in elucidating the underlying cause of cardiac insult and detecting myocardial tissue damage at 24 hr post-treatment. The inter-laboratory and inter-platform comparison analyses also showed that the data obtained from different laboratories and platforms are highly correlated and reproducible, making these biomarkers widely applicable in preclinical studies. PMID:27638646

Hot air impingement on a flat plate using Large Eddy Simulation (LES) technique

NASA Astrophysics Data System (ADS)

Plengsa-ard, C.; Kaewbumrung, M.

2018-01-01

Impinging hot gas jets to a flat plate generate very high heat transfer coefficients in the impingement zone. The magnitude of heat transfer prediction near the stagnation point is important and accurate heat flux distribution are needed. This research studies on heat transfer and flow field resulting from a single hot air impinging wall. The simulation is carried out using computational fluid dynamics (CFD) commercial code FLUENT. Large Eddy Simulation (LES) approach with a subgrid-scale Smagorinsky-Lilly model is present. The classical Werner-Wengle wall model is used to compute the predicted results of velocity and temperature near walls. The Smagorinsky constant in the turbulence model is set to 0.1 and is kept constant throughout the investigation. The hot gas jet impingement on the flat plate with a constant surface temperature is chosen to validate the predicted heat flux results with experimental data. The jet Reynolds number is equal to 20,000 and a fixed jet-to-plate spacing of H/D = 2.0. Nusselt number on the impingement surface is calculated. As predicted by the wall model, the instantaneous computed Nusselt number agree fairly well with experimental data. The largest values of calculated Nusselt number are near the stagnation point and decrease monotonically in the wall jet region. Also, the contour plots of instantaneous values of wall heat flux on a flat plate are captured by LES simulation.

A Copay Foundation Assistance Support Program for Patients Receiving Intravenous Cancer Therapy

PubMed Central

Rajurkar, Swapnil P.; Presant, Cary A.; Bosserman, Linda D.; McNatt, Wendy J.

2011-01-01

Purpose: With the advent of newer cancer therapies (eg, biologic and cytotoxic), treatment is becoming increasingly expensive for patients with cancer. Patients enrolled in Medicare and commercial insurance plans often have large copay requirements with each treatment cycle. Often, these patients undergo significant financial hardship, and some patients decline treatment. We have developed a support program that works closely with all copay assistance foundations to secure financial assistance to facilitate appropriate treatment. Methods: In September, 2008 we initiated a coordinated program with various copay assistance foundations, including Healthwell, Cancer Care, Patient Access, Chronic Disease Fund, Beckstrand Cancer, Lilly Cares and the Leukemia and Lymphoma Society. Patients requesting assistance with chemotherapy copay were enrolled in this program. Information about income level, chemotherapy regimens, and associated copay was given to these foundations, who then determined the amount of monetary assistance. Results: Since the initiation of this program, of 201 patients who began receiving chemotherapy, 25 (12.4%) requested assistance with this program for either intravenous or oral treatments. The current results of time delays for foundation decision, success rates and administrative costs to secure funding will be presented at the time of the poster presentation. Conclusion: Copay for chemotherapy drugs is a financial hardship for a significant number of patients. Coordinated resources must be provided and reimbursed to facilitate appropriate and sustainable cancer care. This program is a successful model for other centers to adopt. PMID:21731517

Improved in silico prediction of carcinogenic potency (TD50) and the risk specific dose (RSD) adjusted Threshold of Toxicological Concern (TTC) for genotoxic chemicals and pharmaceutical impurities.

PubMed

Contrera, Joseph F

2011-02-01

The Threshold of Toxicological Concern (TTC) is a level of exposure to a genotoxic impurity that is considered to represent a negligible risk to humans. The TTC was derived from the results of rodent carcinogenicity TD50 values that are a measure of carcinogenic potency. The TTC currently sets a default limit of 1.5 μg/day in food contact substances and pharmaceuticals for all genotoxic impurities without carcinogenicity data. Bercu et al. (2010) used the QSAR predicted TD50 to calculate a risk specific dose (RSD) which is a carcinogenic potency adjusted TTC for genotoxic impurities. This promising approach is currently limited by the software used, a combination of MC4PC (www.multicase.com) and a Lilly Inc. in-house software (VISDOM) that is not available to the public. In this report the TD50 and RSD were predicted using a commercially available software, SciQSAR (formally MDL-QSAR, www.scimatics.com) employing the same TD50 training data set and external validation test set that was used by Bercu et al. (2010). The results demonstrate the general applicability of QSAR predicted TD50 values to determine the RSDs for genotoxic impurities and the improved performance of SciQSAR for predicting TD50 values. Copyright © 2010 Elsevier Inc. All rights reserved.

Reconnaissance stratigraphy of the Red Glacier Formation (Middle Jurassic) near Hungryman Creek, Cook Inlet basin, Alaska

USGS Publications Warehouse

LePain, D.L.; Stanley, Richard G.; Helmold, K.P.

2016-01-01

Geochemical data suggest the source of oil in upper Cook Inlet fields is Middle Jurassic organic-rich shales in the Tuxedni Group (Magoon and Anders, 1992; Lillis and Stanley, 2011; LePain and others, 2012, 2013). Of the six formations in the group (Detterman, 1963), the basal Red Glacier Formation is the only unit that includes fine-grained rocks in outcrop that appear to be organic-rich (fig. 3-1). In an effort to better understand the stratigraphy and source-rock potential of the Red Glacier Formation, the Alaska Division of Geological & Geophysical Surveys, in collaboration with the Alaska Division of Oil and Gas and the U.S. Geological Survey, has been investigating the unit in outcrop between Tuxedni Bay and the type section at Lateral and Red glaciers (Stanley and others, 2013; LePain and Stanley, 2015; Helmold and others, 2016 [this volume]). Fieldwork in 2015 focused on a southeast-trending ridge south of Hungryman Creek, where the lower 60–70 percent of the formation (400–500 m) is exposed and accessible, except for the near-vertical faces of three segments near the southeast end of the ridge (figs. 3-2 and 3-3). Three stratigraphic sections were measured along the ridge to document facies and depositional environments (figs. 3-3 and 3-4). Steep terrain precluded study of the upper part of the formation exposed east of the ridge. This report includes a preliminary summary of findings from the 2015 field season.

Treatment of clozapine-associated obesity and diabetes with exenatide (CODEX) in adults with schizophrenia: study protocol for a pilot randomised controlled trial.

PubMed

Mayfield, Karla; Siskind, Dan; Winckel, Karl; Hollingworth, Samantha; Kisely, Steve; Russell, Anthony W

2015-06-01

Clozapine causes significant metabolic disturbances including obesity and type 2 diabetes. Recent evidence that reduced glucagon-like-peptide-1 (GLP-1) may contribute to aetiology of clozapine-associated metabolic dysregulation suggests a potential therapeutic role for GLP-1 agonists. This open-label, pilot randomised controlled trial evaluates the effect of exenatide in clozapine-treated obese adults who have schizophrenia, with or without poorly controlled diabetes. Sixty out-patients will be randomised to once weekly extended release exenatide or treatment as usual for 24 weeks. To evaluate the feasibility of larger studies regarding methodology, acceptability, tolerability and estimate efficacy for glycaemic control or weight loss. Secondary outcomes are psychosis severity and metabolic parameters. This is the first trial investigating GLP-1 agonists for glycaemic control and weight loss in clozapine-treated patients with either diabetes or obesity. Clozapine-associated obesity and diabetes with exenatide (CODEX) will provide proof-of-concept empirical evidence addressing whether this novel treatment is practical and worthy of further investigation. A.W.R. has received speaker honoraria and travel grants from AstraZeneca, BoehringerIngelheim, Eli Lilly, MSD, Novo Nordisk and Sanofi and has participated on advisory panels for MSD and Novo Nordisk. © The Royal College of Psychiatrists 2015. This is an open access article distributed under the terms of the Creative Commons Non-Commercial, No Derivatives (CC BY-NC-ND) licence.

Perceptions of Oncologists, Healthcare Policy Makers, Patients and the General Population on the Value of Pharmaceutical Treatments in Oncology.

PubMed

Sacristán, José A; Lizan, Luís; Comellas, Marta; Garrido, Pilar; Avendaño, Cristina; Cruz-Hernández, Juan J; Espinosa, Javier; Dilla, Tatiana

2016-11-01

The purpose of this study was to explore the main factors explaining the relative weight of the different attributes that determine the value of oncologic treatments from the different perspectives of healthcare policy makers (HCPM), oncologists, patients and the general population in Spain. Structured interviews were conducted to assess: (1) the importance of the attributes on treatment choice when comparing a new cancer drug with a standard cancer treatment; (2) the importance of survival, quality of life (QoL), costs and innovation in cancer; and (3) the most worrying side effects related to cancer drugs. A total of 188 individuals participated in the study. For all participants, when choosing treatments, the best rated characteristics were greater efficacy, greater safety, treatment adaptation to patients' individual requirements and the rapid reincorporation of patients to their daily activities. There were important differences among participants in their opinion about survival, QoL and cost. In general, oncologists, patients, and the general population gave greater value to gains in QoL than healthcare policy makers. Compared to other participants healthcare policy makers gave greater importance to the economic impact related to oncology treatments. Gains in QoL, survival, safety, cost and innovation are perceived differently by different groups of stakeholders. It is recommended to consider the perspective of different stakeholders in the assessment of a new cancer drugs to obtain more informed decisions when deciding on the most appropriate treatment to use. Eli Lilly & Co, Madrid (Spain).

Detection of Chlamydophila psittaci from feral pigeons in environmental samples: problems with currently available techniques.

PubMed

Geigenfeind, Ila; Haag-Wackernagel, Daniel

2010-03-01

Chlamydophila psittaci (Lillie, 1930) Everett et al., 1999, the pathogenic agent of human ornithosis, is widespread in feral pigeon populations and many cases of transmission from feral pigeons to humans have been reported. The aim of the present study was to detect C. psittaci in environmental samples to find out more about possible transmission routes and, therefore, to assess the zoonotic risk for humans. Fecal samples were collected from nest boxes in a feral pigeon loft. Additionally, samples were taken from the feather dust film covering the water surface of public fountains where pigeons regularly bathe. The samples were tested for the presence of chlamydial antigen using an antigen enzyme-linked immunosorbent assay to prove shedding of C. psittaci by feral pigeons. This test detects a genus specific lipopolysaccharide in the outer membrane of the chlamydial bacteria. Samples were tested using the IDEIA PCE Chlamydia Test kit (DakoCytomation) and positive results were verified with IDEIA Chlamydia Blocking Reagents (DakoCytomation). The IDEIA PCE Chlamydia Test yields a high proportion of positive results. However, when IDEIA Chlamydia Blocking was performed, most of the positive results turned out to be negative or could not be interpreted. We conclude that antigen-enzyme-linked immunosorbent assay tests are not suitable for detecting C. psittaci in environmental samples. Previous publications where no blocking test was used should be reconsidered critically. © 2010 ISZS, Blackwell Publishing and IOZ/CAS.

Dulaglutide, a long-acting GLP-1 analog fused with an Fc antibody fragment for the potential treatment of type 2 diabetes.

PubMed

Jimenez-Solem, Espen; Rasmussen, Mette H; Christensen, Mikkel; Knop, Filip K

2010-12-01

Dulaglutide (LY-2189265) is a novel, long-acting glucagon-like peptide 1 (GLP-1) analog being developed by Eli Lilly for the treatment of type 2 diabetes mellitus (T2DM). Dulaglutide consists of GLP-1(7-37) covalently linked to an Fc fragment of human IgG4, thereby protecting the GLP-1 moiety from inactivation by dipeptidyl peptidase 4. In vitro and in vivo studies on T2DM models demonstrated glucose-dependent insulin secretion stimulation. Pharmacokinetic studies demonstrated a t1/2 in humans of up to 90 h, making dulaglutide an ideal candidate for once-weekly dosing. Clinical trials suggest that dulaglutide reduces plasma glucose, and has an insulinotropic effect increasing insulin and C-peptide levels. Two phase II clinical trials demonstrated a dose-dependent reduction in glycated hemoglobin (HbA1c) of up to 1.52% compared with placebo. Side effects associated with dulaglutide administration were mainly gastrointestinal. To date, there have been no reports on the formation of antibodies against dulaglutide, but, clearly, long-term data will be needed to asses this and other possible side effects. The results of several phase III clinical trials are awaited for clarification of the expected effects on HbA1c and body weight. If dulaglutide possesses similar efficacy to other GLP-1 analogs, the once-weekly treatment will most likely be welcomed by patients with T2DM.

Real-World Dosing Patterns of Atomoxetine in Adults with Attention-Deficit/Hyperactivity Disorder.

PubMed

Kabul, Samaneh; Alatorre, Carlos; Montejano, Leslie B; Farr, Amanda M; Clemow, David B

2015-12-01

The aim was to investigate the dosing patterns of atomoxetine monotherapy in adult patients with attention-deficit/hyperactivity disorder (ADHD) in a retrospective analysis. Adult (≥ 18 years) patients with ADHD newly initiated on atomoxetine with ≥ 1 outpatient pharmacy claim for atomoxetine between January 2006 and December 2011 were selected from the Truven Health MarketScan(®) Commercial database. After a 30-day titration period, dosing patterns of atomoxetine monotherapy were analyzed in the 12 months following initiation. In addition, patient demographic and clinical characteristics were compared to identify characteristics associated with suboptimal versus recommended dosing. Of the 12,412 adult patients with ADHD newly initiated on atomoxetine, 4548 (36.6%) were suboptimally dosed, whereas 3323 (26.7%) were treated at recommended dose. Overall, study patients were treated at a mean (standard deviation [SD]) dose of 68.5 (44.9) mg/day. The suboptimal dosing cohort included significantly more females (54% vs. 44%, P < 0.001) and had fewer patients with pre-index use of other ADHD medications (17% vs. 20%, P < 0.001) compared with the recommended dosing cohort. Adult patients with ADHD receiving atomoxetine therapy in a real-world setting are often dosed suboptimally. Increasing the awareness on optimal dosing strategy among clinicians and patients is warranted to maximize the therapeutic benefits of atomoxetine among adult patients with ADHD. © 2015 Eli Lilly and Company. CNS Neuroscience and Therapeutics published by John Wiley & Sons Ltd.

Nonclinical pharmacology and toxicology of the first biosimilar insulin glargine drug product (BASAGLAR®/ABASAGLAR®) approved in the European Union.

PubMed

Byrd, Richard A; Owens, Rebecca A; Blackbourne, Jamie L; Coutant, David E; Farmen, Mark W; Michael, M Dodson; Moyers, Julie S; Schultze, A Eric; Sievert, Michael K; Tripathi, Niraj K; Vahle, John L

2017-08-01

Basaglar ® /Abasaglar ® (Lilly insulin glargine [LY IGlar]) is a long-acting human insulin analogue drug product granted marketing authorisation as a biosimilar to Lantus ® (Sanofi insulin glargine [SA IGlar]) by the European Medicines Agency. We assessed the similarity of LY IGlar to the reference drug product, European Union-sourced SA IGlar (EU-SA IGlar), using nonclinical in vitro and in vivo studies. No biologically relevant differences were observed for receptor binding affinity at either the insulin or insulin-like growth factor-1 (IGF-1) receptors, or in assays of functional or de novo lipogenic activity. The mitogenic potential of LY IGlar and EU-SA IGlar was similar when tested in both insulin- and IGF-1 receptor dominant cell systems. Repeated subcutaneous daily dosing of rats for 4 weeks with 0, 0.3, 1.0, or 2.0 mg/kg LY IGlar and EU-SA IGlar produced mortalities and clinical signs consistent with severe hypoglycaemia. Glucodynamic profiles of LY IGlar and EU-SA IGlar in satellite animals showed comparable dose-related hypoglycaemia. Severe hypoglycaemia was associated with axonal degeneration of the sciatic nerve; the incidence and severity were low and did not differ between LY IGlar and EU-SA IGlar. These results demonstrated no biologically relevant differences in toxicity between LY IGlar and EU-SA IGlar. Copyright © 2017 Elsevier Inc. All rights reserved.

Control of galactosylated glycoforms distribution in cell culture system.

PubMed

McCracken, Neil A; Kowle, Ronald; Ouyang, Anli

2014-01-01

Cell culture process conditions including media components and bioreactor operation conditions have a profound impact on recombinant protein quality attributes. Considerable changes in the distribution of galactosylated glycoforms (G0F, G1F, and G2F) were observed across multiple CHO derived recombinant proteins in development at Eli Lilly and Company when switching to a new chemically defined (CD) media platform condition. In the new CD platform, significantly lower G0F percentages and higher G1F and G2F were observed. These changes were of interest as glycosylation heterogeneity can impact the effectiveness of a protein. A systematic investigation was done to understand the root cause of the change and control strategy for galactosylated glycoforms distribution. It was found that changes in asparagine concentration could result in a corresponding change in G0F, G1F, and G2F distribution. A follow-up study examined a wider range of asparagine concentration and it was found that G0F, G1F, and G2F percentage could be titrated by adjusting asparagine concentration. The observed changes in heterogeneity from changing asparagine concentration are due to resulting changes in ammonium metabolism. Further study ascertained that different integrated ammonium level during the cell culture process could control G0F, G1F, and G2F percentage distribution. A mechanism hypothesis is proposed that integrated ammonium level impacts intracellular pH, which further regulates β-1, 4 galactosyltransferase activity. © 2014 American Institute of Chemical Engineers.

Proton milliprobe analyses of the Gutenberg Bible

NASA Astrophysics Data System (ADS)

Kusko, Bruce H.; Cahill, Thomas A.; Eldred, Robert A.; Schwab, Richard N.

1984-04-01

The advent of printing with movable type is properly regarded as the most important technological event in modern cultural history, yet its earliest history is shrouded in mystery. The Davis proton milliprobe has enabled scientists and humanist scholars to collaborate in unlocking the secrets of earliest print, focusing on the contribution of Johannes Gutenberg. The 42-line Gutenberg Bible is not only the first book printed by movable type, it is considered by many to be the finest book every printed. Unfortunately very little is known about the materials and techniques used in this first large scale printing operation. In October 1982 we had the unprecedented opportunity to examine page-by-page the inks, papers, illuminations and binding of volume I of the Doheny Gutenberg Bible. A similar study of the Lilly New Testament (most of volume II) was undertaken in March 1983. The results, some wholly unexpected and very exciting, add a large new body of information about this great work, and give us new enlightenment on the day-to-day production of this first and most important printed book. Moreover, the discovery of the uniqueness of the ink in Gutenberg's Bible, combined with our ability to taken minutely detailed and non-destructive elemental "fingerprints" with the milliprobe beam of all man-made papers and inks, gives us a weapon that has never been available before to investigate some of the controversial basic questions in the history of the origins of printing technology.

Pharma Success in Product Development—Does Biotechnology Change the Paradigm in Product Development and Attrition.

PubMed

Evens, Ronald P

2016-01-01

The biotechnology segment of the overall biopharma industry has existed for only about 40–45 years, as a driver of new product development. This driving force was initiated with the FDA approval of recombinant human insulin in 1982, originating from the Genentech company. The pharma industry in the early years of 1970s and 1980s engaged with biotechnology companies only to a small extent with their in-licensing of a few recombinant molecules, led by Roche, Eli Lilly, and Johnson and Johnson. However, subsequently and dramatically over the last 25 years, biotechnology has become a primary driver of product and technology innovation and has become a cornerstone in new product development by all biopharma companies. This review demonstrates these evolutionary changes regarding approved products, product pipelines, novelty of the products, FDA approval rates, product sales, financial R&D investments in biotechnology, partnerships, mergers and acquisitions, and patent issues. We now have about 300 biotechnology products approved in USA covering 16 medical disciplines and about 250 indications, with the engagement of 25 pharma companies, along with their biotechnology company innovators and partners. The biotechnology pipeline involves over 1000 molecules in clinical trials, including over 300 molecules associated with the top 10 pharma companies. Product approval rates by the FDA for biotechnology products are over double the rate for drugs. Yes, the R&D paradigm has changed with biotechnology now as one of the major focuses for new product development with novel molecules by the whole biopharma industry.

Evaluation of Cardiac Toxicity Biomarkers in Rats from Different Laboratories.

PubMed

Kim, Kyuri; Chini, Naseem; Fairchild, David G; Engle, Steven K; Reagan, William J; Summers, Sandra D; Mirsalis, Jon C

2016-12-01

There is a great need for improved diagnostic and prognostic accuracy of potential cardiac toxicity in drug development. This study reports the evaluation of several commercially available biomarker kits by 3 institutions (SRI, Eli Lilly, and Pfizer) for the discrimination between myocardial degeneration/necrosis and cardiac hypertrophy as well as the assessment of the interlaboratory and interplatform variation in results. Serum concentrations of natriuretic peptides (N-terminal pro-atrial natriuretic peptide [NT-proANP] and N-terminal pro-brain natriuretic peptide [NT-proBNP]), cardiac and skeletal troponins (cTnI, cTnT, and sTnI), myosin light chain 3 (Myl3), and fatty acid binding protein 3 (FABP3) were assessed in rats treated with minoxidil (MNX) and isoproterenol (ISO). MNX caused increased heart-to-body weight ratios and prominent elevations in NT-proANP and NT-proBNP concentrations detected at 24-hr postdose without elevation in troponins, Myl3, or FABP3 and with no abnormal histopathological findings. ISO caused ventricular leukocyte infiltration, myocyte fibrosis, and necrosis with increased concentrations of the natriuretic peptides, cardiac troponins, and Myl3. These results reinforce the advantages of a multimarker strategy in elucidating the underlying cause of cardiac insult and detecting myocardial tissue damage at 24-hr posttreatment. The interlaboratory and interplatform comparison analyses also showed that the data obtained from different laboratories and platforms are highly correlated and reproducible, making these biomarkers widely applicable in preclinical studies.

The Cultural Epigenesis of Gender-Based Violence in Cambodia: Local and Buddhist Perspectives.

PubMed

Eisenbruch, Maurice

2018-06-01

Almost one in four women in Cambodia is a victim of physical, emotional or sexual violence. The study aims to provide a comprehensive understanding of the ways in which Cambodians see its causes and effects and to identify and analyse the cultural forces that underpin and shape its landscape. An ethnographic study was carried out with 102 perpetrators and survivors of emotional, physical and sexual violence against women and 228 key informants from the Buddhist and healing sectors. Their views and experiences of it were recorded-the popular idioms expressed and the symptoms of distress experienced by survivors and perpetrators. From these results, the eight cultural forces, or cultural attractors, that are seen to propel a person to violence were identified. Violence stemmed from blighted endowment, or 'bad building' (sɑmnaaŋ mɨn lʔɑɑ) determined by deeds in a previous life (kam). Children with a vicious character (kmeeŋ kaac or doṣa-carita) might grow to be abusers, and particular birthmarks on boys were thought to be portents. Krʊəh, or mishap, especially when a female's horoscope predicted a zodiac house on the descent (riesəy), explained vulnerability to violence and its timing. Astrological incompatibility (kuu kam) was a risk factor. Lust, anger and ignorance, the 'Triple Poison', fuelled it. 'Entering the road to ruin' (apāyamuk), including alcohol abuse, womanising and gambling, triggered it. Confusion and loss of judgement (mohā) led to moral blindness (mo baŋ). These were the eight cultural attractors that shaped the landscape of violence against women. The cultural epigenesis of violence against women in Cambodia is an insight which can be used to build culturally responsive interventions and strengthen the primary prevention of violence against women. An understanding of the epigenesis of violence could strengthen the primary prevention of violence against women.

Do conceptualisations of health differ across social strata? A concept mapping study among lay people.

PubMed

Stronks, Karien; Hoeymans, Nancy; Haverkamp, Beatrijs; den Hertog, Frank R J; van Bon-Martens, Marja J H; Galenkamp, Henrike; Verweij, Marcel; van Oers, Hans A M

2018-04-19

The legitimacy of policies that aim at tackling socioeconomic inequalities in health can be challenged if they do not reflect the conceptualisations of health that are valued in all strata. Therefore, this study analyses how different socioeconomic groups formulate their own answers regarding: what does health mean to you? Concept mapping procedures were performed in three groups that differ in educational level. All procedures followed exactly the same design. Area of the city of Utrecht, the Netherlands. Lay persons with a lower, intermediate and higher educational level (±15/group). The concept maps for the three groups consisted of nine, eight and seven clusters each, respectively. Four clusters occurred in all groups: absence of disease/disabilities, health-related behaviours, social life, attitude towards life. The content of some of these differed between groups, for example, behaviours were interpreted as having opportunities to behave healthily in the lower education group, and in terms of their impact on health in the higher education group. Other clusters appeared to be specific for particular groups, such as autonomy (intermediate/higher education group). Finally, ranking ranged from a higher ranking of the positively formulated aspects in the higher education group (eg, lust for life) to that of the negatively formulated aspects in the lower education group (eg, having no chronic disease). Our results provide indications to suggest that people in lower socioeconomic groups are more likely to show a conceptualisation of health that refers to (1) the absence of health threats (vs positive aspects), (2) a person within his/her circumstances (vs quality of own body/mind), (3) the value of functional (vs hedonistic) notions and (4) an accepting (vs active) attitude towards life. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

SU-F-I-37: How Fat Distribution and Table Height Affect Estimates of Patient Size in CT Scanning: A Phantom Study

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

Silosky, M; Marsh, R

Purpose: Localizer projection radiographs acquired prior to CT scans are used to estimate patient size, affecting the function of Automatic Tube Current Modulation (ATCM) and hence CTDIvol and SSDE. Due to geometric effects, the projected patient size varies with scanner table height and with the orientation of the localizer (AP versus PA). This study sought to determine if patient size estimates made from localizer scans is affected by variations in fat distribution, specifically when the widest part of the patient is not at the geometric center of the patient. Methods: Lipid gel bolus material was wrapped around an anthropomorphic phantommore » to simulate two different body mass distributions. The first represented a patient with fairly rigid fat and had a generally oval shape. The second was bell-shaped, representing corpulent patients more susceptible to gravity’s lustful tug. Each phantom configuration was imaged using an AP localizer and then a PA localizer. This was repeated at various scanner table heights. The width of the phantom was measured from the localizer and diagnostic images using in-house software. Results: 1) The projected phantom width varied up to 39% as table height changed.2) At some table heights, the width of the phantom, designed to represent larger patients, exceeded the localizer field of view, resulting in an underestimation of the phantom width.3) The oval-shaped phantom approached a normalized phantom width of 1 at a table height several centimeters lower (AP localizer) or higher (PA localizer) than did the bell-shaped phantom. Conclusion: Accurate estimation of patient size from localizer scans is dependent on patient positioning with respect to scanner isocenter and is limited in large patients. Further, patient size is more accurately measured on projection images if the widest part of the patient, rather than the geometric center of the patient, is positioned at scanner isocenter.« less

The Agreement between Auscultation and Lung Ultrasound in Hemodialysis Patients: The LUST Study.

PubMed

Torino, Claudia; Gargani, Luna; Sicari, Rosa; Letachowicz, Krzysztof; Ekart, Robert; Fliser, Danilo; Covic, Adrian; Siamopoulos, Kostas; Stavroulopoulos, Aristeidis; Massy, Ziad A; Fiaccadori, Enrico; Caiazza, Alberto; Bachelet, Thomas; Slotki, Itzchak; Martinez-Castelao, Alberto; Coudert-Krier, Marie-Jeanne; Rossignol, Patrick; Gueler, Faikah; Hannedouche, Thierry; Panichi, Vincenzo; Wiecek, Andrzej; Pontoriero, Giuseppe; Sarafidis, Pantelis; Klinger, Marian; Hojs, Radovan; Seiler-Mussler, Sarah; Lizzi, Fabio; Siriopol, Dimitrie; Balafa, Olga; Shavit, Linda; Tripepi, Rocco; Mallamaci, Francesca; Tripepi, Giovanni; Picano, Eugenio; London, Gérard Michel; Zoccali, Carmine

2016-11-07

Accumulation of fluid in the lung is the most concerning sequela of volume expansion in patients with ESRD. Lung auscultation is recommended to detect and monitor pulmonary congestion, but its reliability in ESRD is unknown. In a subproject of the ongoing Lung Water by Ultra-Sound Guided Treatment to Prevent Death and Cardiovascular Complications in High Risk ESRD Patients with Cardiomyopathy Trial, we compared a lung ultrasound-guided ultrafiltration prescription policy versus standard care in high-risk patients on hemodialysis. The reliability of peripheral edema was tested as well. This study was on the basis of 1106 pre- and postdialysis lung ultrasound studies (in 79 patients) simultaneous with standardized lung auscultation (crackles at the lung bases) and quantification of peripheral edema. Lung congestion by crackles, edema, or a combination thereof poorly reflected the severity of congestion as detected by ultrasound B lines in various analyses, including standard regression analysis weighting for repeated measures in individual patients (shared variance of 12% and 4% for crackles and edema, respectively) and κ-statistics (κ ranging from 0.00 to 0.16). In general, auscultation had very low discriminatory power for the diagnosis of mild (area under the receiver operating curve =0.61), moderate (area under the receiver operating curve =0.65), and severe (area under the receiver operating curve =0.68) lung congestion, and the same was true for peripheral edema (receiver operating curve =0.56 or lower) and the combination of the two physical signs. Lung crackles, either alone or combined with peripheral edema, very poorly reflect interstitial lung edema in patients with ESRD. These findings reinforce the rationale underlying the Lung Water by Ultra-Sound Guided Treatment to Prevent Death and Cardiovascular Complications in High Risk ESRD Patients with Cardiomyopathy Trial, a trial adopting ultrasound B lines as an instrument to guide interventions aimed at mitigating lung congestion in high-risk patients on hemodialysis. Copyright © 2016 by the American Society of Nephrology.

The Agreement between Auscultation and Lung Ultrasound in Hemodialysis Patients: The LUST Study

PubMed Central

Torino, Claudia; Gargani, Luna; Sicari, Rosa; Letachowicz, Krzysztof; Ekart, Robert; Fliser, Danilo; Covic, Adrian; Siamopoulos, Kostas; Stavroulopoulos, Aristeidis; Massy, Ziad A.; Fiaccadori, Enrico; Caiazza, Alberto; Bachelet, Thomas; Slotki, Itzchak; Martinez-Castelao, Alberto; Coudert-Krier, Marie-Jeanne; Rossignol, Patrick; Gueler, Faikah; Hannedouche, Thierry; Panichi, Vincenzo; Wiecek, Andrzej; Pontoriero, Giuseppe; Sarafidis, Pantelis; Klinger, Marian; Hojs, Radovan; Seiler-Mussler, Sarah; Lizzi, Fabio; Siriopol, Dimitrie; Balafa, Olga; Shavit, Linda; Tripepi, Rocco; Mallamaci, Francesca; Tripepi, Giovanni; Picano, Eugenio; London, Gérard Michel

2016-01-01

Background and objectives Accumulation of fluid in the lung is the most concerning sequela of volume expansion in patients with ESRD. Lung auscultation is recommended to detect and monitor pulmonary congestion, but its reliability in ESRD is unknown. Design, setting, participants, & measurements In a subproject of the ongoing Lung Water by Ultra-Sound Guided Treatment to Prevent Death and Cardiovascular Complications in High Risk ESRD Patients with Cardiomyopathy Trial, we compared a lung ultrasound–guided ultrafiltration prescription policy versus standard care in high-risk patients on hemodialysis. The reliability of peripheral edema was tested as well. This study was on the basis of 1106 pre– and postdialysis lung ultrasound studies (in 79 patients) simultaneous with standardized lung auscultation (crackles at the lung bases) and quantification of peripheral edema. Results Lung congestion by crackles, edema, or a combination thereof poorly reflected the severity of congestion as detected by ultrasound B lines in various analyses, including standard regression analysis weighting for repeated measures in individual patients (shared variance of 12% and 4% for crackles and edema, respectively) and κ-statistics (κ ranging from 0.00 to 0.16). In general, auscultation had very low discriminatory power for the diagnosis of mild (area under the receiver operating curve =0.61), moderate (area under the receiver operating curve =0.65), and severe (area under the receiver operating curve =0.68) lung congestion, and the same was true for peripheral edema (receiver operating curve =0.56 or lower) and the combination of the two physical signs. Conclusions Lung crackles, either alone or combined with peripheral edema, very poorly reflect interstitial lung edema in patients with ESRD. These findings reinforce the rationale underlying the Lung Water by Ultra-Sound Guided Treatment to Prevent Death and Cardiovascular Complications in High Risk ESRD Patients with Cardiomyopathy Trial, a trial adopting ultrasound B lines as an instrument to guide interventions aimed at mitigating lung congestion in high-risk patients on hemodialysis. PMID:27660305

Cross-Species Affective Neuroscience Decoding of the Primal Affective Experiences of Humans and Related Animals

PubMed Central

Panksepp, Jaak

2011-01-01

Background The issue of whether other animals have internally felt experiences has vexed animal behavioral science since its inception. Although most investigators remain agnostic on such contentious issues, there is now abundant experimental evidence indicating that all mammals have negatively and positively-valenced emotional networks concentrated in homologous brain regions that mediate affective experiences when animals are emotionally aroused. That is what the neuroscientific evidence indicates. Principal Findings The relevant lines of evidence are as follows: 1) It is easy to elicit powerful unconditioned emotional responses using localized electrical stimulation of the brain (ESB); these effects are concentrated in ancient subcortical brain regions. Seven types of emotional arousals have been described; using a special capitalized nomenclature for such primary process emotional systems, they are SEEKING, RAGE, FEAR, LUST, CARE, PANIC/GRIEF and PLAY. 2) These brain circuits are situated in homologous subcortical brain regions in all vertebrates tested. Thus, if one activates FEAR arousal circuits in rats, cats or primates, all exhibit similar fear responses. 3) All primary-process emotional-instinctual urges, even ones as complex as social PLAY, remain intact after radical neo-decortication early in life; thus, the neocortex is not essential for the generation of primary-process emotionality. 4) Using diverse measures, one can demonstrate that animals like and dislike ESB of brain regions that evoke unconditioned instinctual emotional behaviors: Such ESBs can serve as ‘rewards’ and ‘punishments’ in diverse approach and escape/avoidance learning tasks. 5) Comparable ESB of human brains yield comparable affective experiences. Thus, robust evidence indicates that raw primary-process (i.e., instinctual, unconditioned) emotional behaviors and feelings emanate from homologous brain functions in all mammals (see Appendix S1), which are regulated by higher brain regions. Such findings suggest nested-hierarchies of BrainMind affective processing, with primal emotional functions being foundational for secondary-process learning and memory mechanisms, which interface with tertiary-process cognitive-thoughtful functions of the BrainMind. PMID:21915252

A Single Dose, Randomized, Controlled Proof-Of-Mechanism Study of a Novel Vasopressin 1a Receptor Antagonist (RG7713) in High-Functioning Adults with Autism Spectrum Disorder.

PubMed

Umbricht, Daniel; Del Valle Rubido, Marta; Hollander, Eric; McCracken, James T; Shic, Frederick; Scahill, Lawrence; Noeldeke, Jana; Boak, Lauren; Khwaja, Omar; Squassante, Lisa; Grundschober, Christophe; Kletzl, Heidemarie; Fontoura, Paulo

2017-08-01

The core symptoms of autism spectrum disorder (ASD) include impaired social communication, repetitive behaviors, and restricted interests. No effective pharmacotherapy for these core deficits exists. Within the domain of social communication, the vasopressin system is implicated in social cognition and social signaling deficits of ASD, and represents a potential therapeutic target. We assessed the effects of a single 20 mg intravenous dose of the arginine vasopressin receptor 1A (V1a) antagonist, RG7713, on exploratory biomarkers (eye tracking), behavioral and clinical measures of social cognition and communication (affective speech recognition (ASR), reading the mind in the eyes, olfactory identification, scripted interaction), and safety and tolerability in a multicenter, randomized, double-blind, placebo-controlled, cross-over study of 19 high-functioning adult male subjects with DSM-IV Autistic Disorder (age 18-45 years; full scale IQ >70; ABC-Irritability subscale ⩽13). Eye-tracking showed an increase in biological motion orienting preference with RG7713 (ES=0.8, p=0.047) and a non-significant improvement in the composite score (ES=0.2, p=0.29). RG7713 reduced ability to detect lust (ES=-0.8, p=0.03) and fear (ES=-0.7, p=0.07) in ASR. However, when all eight individual emotion subscales were combined into an overall ASR performance score, the reduction was non-significant (ES=-0.1, p=0.59). Thirteen adverse events were reported in 10 subjects; all were of mild (11/13) or moderate (2/13) severity. Although interpretation should be cautious due to multiple comparisons and small sample size, these results provide preliminary evidence from experimental and behavioral biomarkers, that blockade of the V1a receptor may improve social communication in adults with high-functioning ASD. ClinicalTrials.gov identifier: NCT01474278 A Study of RO5028442 in Adult Male High-Functioning Autistic Patients. Available at: https://clinicaltrials.gov/ct2/show/NCT01474278.

Female youth who sexually coerce: prevalence, risk, and protective factors in two national high school surveys.

PubMed

Kjellgren, Cecilia; Priebe, Gisela; Svedin, Carl Göran; Mossige, Svein; Långström, Niklas

2011-12-01

Sexual coercion is recognized as a serious societal problem. Correlates and risk factors of sexually abusive behavior in females are not well known. Etiological theory and empirical study of female perpetrators of sexual coercion are usually based on small or highly selected samples. Specifically, population-based data are needed to elucidate risk/protective factors. Main outcome measures include a self-report questionnaire containing 65 items tapping socio-demographic and health conditions, social relations, sexual victimization, conduct problems and a set of normative and deviant sexual cognitions, attitudes, and behaviors. We used a 2003-2004 survey of sexual attitudes and experiences among high school students in Norway and Sweden to identify risk factors and correlates to sexually coercive behavior (response rate 80%); 4,363 females participated (Mean = 18.1 years). Thirty-seven women (0.8%) reported sexual coercion (ever talked someone into, used pressure, or forced somebody to have sex). Sexually coercive compared with non-coercive women were similar on socio-demographic variables, but reported less parental care and more parental overprotection, aggression, depressive symptoms, and substance misuse. Also, sexually coercive females reported more sexual lust, sex partners, penetrative sexual victimization, rape myths, use of violent porn, and friends more likely to use porn. When using the Swedish subsample to differentiate risk factors specific for sexual coercion from those for antisocial behavior in general, we found less cannabis use, but more sexual preoccupation, pro-rape attitudes, and friends using violent porn in sexually coercive compared with non-sex conduct problem females. Sexually coercive behavior in high school women was associated with general risk/needs factors for antisocial behavior, but also with specific sexuality-related risk factors. This differential effect has previously been overlooked, agrees with similar findings in men, and should have substantial etiological importance. © 2009 International Society for Sexual Medicine.

Cross-species affective neuroscience decoding of the primal affective experiences of humans and related animals.

PubMed

Panksepp, Jaak

2011-01-01

The issue of whether other animals have internally felt experiences has vexed animal behavioral science since its inception. Although most investigators remain agnostic on such contentious issues, there is now abundant experimental evidence indicating that all mammals have negatively and positively-valenced emotional networks concentrated in homologous brain regions that mediate affective experiences when animals are emotionally aroused. That is what the neuroscientific evidence indicates. The relevant lines of evidence are as follows: 1) It is easy to elicit powerful unconditioned emotional responses using localized electrical stimulation of the brain (ESB); these effects are concentrated in ancient subcortical brain regions. Seven types of emotional arousals have been described; using a special capitalized nomenclature for such primary process emotional systems, they are SEEKING, RAGE, FEAR, LUST, CARE, PANIC/GRIEF and PLAY. 2) These brain circuits are situated in homologous subcortical brain regions in all vertebrates tested. Thus, if one activates FEAR arousal circuits in rats, cats or primates, all exhibit similar fear responses. 3) All primary-process emotional-instinctual urges, even ones as complex as social PLAY, remain intact after radical neo-decortication early in life; thus, the neocortex is not essential for the generation of primary-process emotionality. 4) Using diverse measures, one can demonstrate that animals like and dislike ESB of brain regions that evoke unconditioned instinctual emotional behaviors: Such ESBs can serve as 'rewards' and 'punishments' in diverse approach and escape/avoidance learning tasks. 5) Comparable ESB of human brains yield comparable affective experiences. Thus, robust evidence indicates that raw primary-process (i.e., instinctual, unconditioned) emotional behaviors and feelings emanate from homologous brain functions in all mammals (see Appendix S1), which are regulated by higher brain regions. Such findings suggest nested-hierarchies of BrainMind affective processing, with primal emotional functions being foundational for secondary-process learning and memory mechanisms, which interface with tertiary-process cognitive-thoughtful functions of the BrainMind.

Reading the mind in the touch: Neurophysiological specificity in the communication of emotions by touch.

PubMed

Kirsch, Louise P; Krahé, Charlotte; Blom, Nadia; Crucianelli, Laura; Moro, Valentina; Jenkinson, Paul M; Fotopoulou, Aikaterini

2017-05-29

Touch is central to interpersonal interactions. Touch conveys specific emotions about the touch provider, but it is not clear whether this is a purely socially learned function or whether it has neurophysiological specificity. In two experiments with healthy participants (N = 76 and 61) and one neuropsychological single case study, we investigated whether a type of touch characterised by peripheral and central neurophysiological specificity, namely the C tactile (CT) system, can communicate specific emotions and mental states. We examined the specificity of emotions elicited by touch delivered at CT-optimal (3cm/s) and CT-suboptimal (18cm/s) velocities (Experiment 1) at different body sites which contain (forearm) vs. do not contain (palm of the hand) CT fibres (Experiment 2). Blindfolded participants were touched without any contextual cues, and were asked to identify the touch provider's emotion and intention. Overall, CT-optimal touch (slow, gentle touch on the forearm) was significantly more likely than other types of touch to convey arousal, lust or desire. Affiliative emotions such as love and related intentions such as social support were instead reliably elicited by gentle touch, irrespective of CT-optimality, suggesting that other top-down factors contribute to these aspects of tactile social communication. To explore the neural basis of this communication, we also tested this paradigm in a stroke patient with right perisylvian damage, including the posterior insular cortex, which is considered as the primary cortical target of CT afferents, but excluding temporal cortex involvement that has been linked to more affiliative aspects of CT-optimal touch. His performance suggested an impairment in 'reading' emotions based on CT-optimal touch. Taken together, our results suggest that the CT system can add specificity to emotional and social communication, particularly with regards to feelings of desire and arousal. On the basis of these findings, we speculate that its primary functional role may be to enhance the 'sensual salience' of tactile interactions. Copyright © 2017. Published by Elsevier Ltd.

The right to protection from sexual assault: the Indian anti-rape campaign.

PubMed

Gangoli, G

1996-11-01

This article reveals a viewpoint that emphasizes some dilemmas among Indian feminist practice, women's sexuality in legal terms, and case law in India. The Indian Women's Movement (IWM) was successful in 1983 in adding a legal amendment on rape and child abuse. The case that mobilized women to change the law occurred in 1980 when a court acquitted two policemen who were charged with raping and molesting a 16-year-old tribal girl. The Bombay High Court overturned the judgement and convicted both policemen. The case was appealed, and the policemen successfully argued that rape did not occur because the girl did not protest and was sexually experienced anyway. In 1980 the Forum Against Rape was formed to mobilize public support and to lobby the State for reform of the law on rape. The campaign focused on custodial rape and political repression, rape as civil rights issue, and rape as a women's issue. There was a distancing between the victim, who occupied a lower caste and class position, and her defenders in the women's groups. The campaign appealed to both the appropriate judgement of the State and the denial that the State was an effective vehicle for change. The campaign did not directly address incest and marital rape or domestic violence within families. The legislature debated the issue of legal change during 1982. The debate revealed deep divisions about sexuality and women's status. It was argued that chaste women were not rape victims, and unchaste women were of a socially inferior caste and class. It was argued that there should be a ban on child marriage rather than spousal rape laws. Child rape is a legal issue only when the perpetrator is outside the family. Rape was discussed as an act of lust and not violence. In 1992, a woman promoting an end to child marriage was raped and the men were acquitted. It was argued that the law was out-of-date and in need of revision.

Developability assessment of clinical drug products with maximum absorbable doses.

PubMed

Ding, Xuan; Rose, John P; Van Gelder, Jan

2012-05-10

Maximum absorbable dose refers to the maximum amount of an orally administered drug that can be absorbed in the gastrointestinal tract. Maximum absorbable dose, or D(abs), has proved to be an important parameter for quantifying the absorption potential of drug candidates. The purpose of this work is to validate the use of D(abs) in a developability assessment context, and to establish appropriate protocol and interpretation criteria for this application. Three methods for calculating D(abs) were compared by assessing how well the methods predicted the absorption limit for a set of real clinical candidates. D(abs) was calculated for these clinical candidates by means of a simple equation and two computer simulation programs, GastroPlus and an program developed at Eli Lilly and Company. Results from single dose escalation studies in Phase I clinical trials were analyzed to identify the maximum absorbable doses for these compounds. Compared to the clinical results, the equation and both simulation programs provide conservative estimates of D(abs), but in general D(abs) from the computer simulations are more accurate, which may find obvious advantage for the simulations in developability assessment. Computer simulations also revealed the complex behavior associated with absorption saturation and suggested in most cases that the D(abs) limit is not likely to be achieved in a typical clinical dose range. On the basis of the validation findings, an approach is proposed for assessing absorption potential, and best practices are discussed for the use of D(abs) estimates to inform clinical formulation development strategies. Copyright © 2012 Elsevier B.V. All rights reserved.

Dynamic Turbulence Modelling in Large-eddy Simulations of the Cloud-topped Atmospheric Boundary Layer

NASA Technical Reports Server (NTRS)

Kirkpatrick, M. P.; Mansour, N. N.; Ackerman, A. S.; Stevens, D. E.

2003-01-01

The use of large eddy simulation, or LES, to study the atmospheric boundary layer dates back to the early 1970s when Deardor (1972) used a three-dimensional simulation to determine velocity and temperature scales in the convective boundary layer. In 1974 he applied LES to the problem of mixing layer entrainment (Deardor 1974) and in 1980 to the cloud-topped boundary layer (Deardor 1980b). Since that time the LES approach has been applied to atmospheric boundary layer problems by numerous authors. While LES has been shown to be relatively robust for simple cases such as a clear, convective boundary layer (Mason 1989), simulation of the cloud-topped boundary layer has proved more of a challenge. The combination of small length scales and anisotropic turbulence coupled with cloud microphysics and radiation effects places a heavy burden on the turbulence model, especially in the cloud-top region. Consequently, over the past few decades considerable effort has been devoted to developing turbulence models that are better able to parameterize these processes. Much of this work has involved taking parameterizations developed for neutral boundary layers and deriving corrections to account for buoyancy effects associated with the background stratification and local buoyancy sources due to radiative and latent heat transfer within the cloud (see Lilly 1962; Deardor 1980a; Mason 1989; MacVean & Mason 1990, for example). In this paper we hope to contribute to this effort by presenting a number of turbulence models in which the model coefficients are calculated dynamically during the simulation rather than being prescribed a priori.

Fjordic Environments of Scotland: A National Inventory of Sedimentary Blue Carbon.

NASA Astrophysics Data System (ADS)

Smeaton, Craig; Austin, William; Davies, Althea; Baltzer, Agnes; Howe, John

2016-04-01

Coastal sediments potentially hold a significant store of carbon; yet there has been no comprehensive attempt to quantitatively determine the quantity of carbon in these stores. Using Scottish sea lochs (fjords) we have established a Holocene record of the quantity and type of carbon held within the sediment store of a typical Scottish sea loch. Through the use of both seismic geophysics and geochemical measurements we have developed a methodology to make first-order estimations of the carbon held with the sediment of sea lochs. This methodology was applied to four sea lochs with differing geographical locations, catchments, freshwater inputs to produce the first sedimentary Blue Carbon estimates. The resulting carbon inventories show clearly that these sea lochs hold a significant store of sedimentary carbon; for example, Loch Sunart in Argyll stores an estimated 26.88 ± 0.52 Mt C. A direct comparison of the organic carbon content per unit area suggest sea lochs have a greater OC storage potential between than Scottish peatlands on long, Holocene timescales (Loch Sunart = 0.234 Mt OC km-2; Peatland = 0.093 Mt OC km-2 (Chapman et al. 2009). The carbon values calculated for these sea lochs have been used to estimate the total carbon held within Scotland's 110 sea lochs and these up-scaled estimations are for the first time, reviewed in the context of Scotland's known terrestrial stores. Chapman, S. J., Bell, J., Donnelly, D. and Lilly, A.: Carbon stocks in Scottish peatlands, Soil Use Manag., 25(2), 105-112, doi:10.1111/j.1475-2743.2009.00219.x, 2009.

Amyloid-ß-directed immunotherapy for Alzheimer's disease

PubMed Central

Lannfelt, L; Relkin, N R; Siemers, E R

2014-01-01

Lannfelt L, Relkin NR, Siemers ER (Uppsala University, Uppsala, Sweden; Weill Cornell Medical College, New York, NY; and Eli Lilly and Co., Indianapolis, IN, USA). Amyloid-ß-directed immunotherapy for Alzheimer’s disease. (Key Symposium). J Intern Med 2014; 275: 284–295. Current treatment options for Alzheimer's disease (AD) are limited to medications that reduce dementia symptoms. Given the rapidly ageing populations in most areas of the world, new therapeutic interventions for AD are urgently needed. In recent years, a number of drug candidates targeting the amyloid-ß (Aß) peptide have advanced into clinical trials; however, most have failed because of safety issues or lack of efficacy. The Aß peptide is central to the pathogenesis, and immunotherapy against Aß has attracted considerable interest. It offers the possibility to reach the target with highly specific drugs. Active immunization and passive immunization have been the most widely studied approaches to immunotherapy of AD. A favourable aspect of active immunization is the capacity for a small number of vaccinations to generate a prolonged antibody response. A potential disadvantage is the variability in the antibody response across patients. The potential advantages of passive immunotherapy include the reproducible delivery of a known amount of therapeutic antibodies to the patient and rapid clearance of those antibodies if side effects develop. A disadvantage is the requirement for repeated infusions of antibodies over time. After more than a decade of research, anti-amyloid immunotherapy remains one of the most promising emerging strategies for developing disease-modifying treatments for AD. In this review, we examine the presently ongoing Aß-directed immunotherapies that have passed clinical development Phase IIa. PMID:24605809

Stabilized high-order Galerkin methods based on a parameter-free dynamic SGS model for LES

NASA Astrophysics Data System (ADS)

Marras, Simone; Nazarov, Murtazo; Giraldo, Francis X.

2015-11-01

The high order spectral element approximation of the Euler equations is stabilized via a dynamic sub-grid scale model (Dyn-SGS). This model was originally designed for linear finite elements to solve compressible flows at large Mach numbers. We extend its application to high-order spectral elements to solve the Euler equations of low Mach number stratified flows. The major justification of this work is twofold: stabilization and large eddy simulation are achieved via one scheme only. Because the diffusion coefficients of the regularization stresses obtained via Dyn-SGS are residual-based, the effect of the artificial diffusion is minimal in the regions where the solution is smooth. The direct consequence is that the nominal convergence rate of the high-order solution of smooth problems is not degraded. To our knowledge, this is the first application in atmospheric modeling of a spectral element model stabilized by an eddy viscosity scheme that, by construction, may fulfill stabilization requirements, can model turbulence via LES, and is completely free of a user-tunable parameter. From its derivation, it will be immediately clear that Dyn-SGS is independent of the numerical method; it could be implemented in a discontinuous Galerkin, finite volume, or other environments alike. Preliminary discontinuous Galerkin results are reported as well. The straightforward extension to non-linear scalar problems is also described. A suite of 1D, 2D, and 3D test cases is used to assess the method, with some comparison against the results obtained with the most known Lilly-Smagorinsky SGS model.

[Psychomotor reaction in primates placed in ballistic flight in rockets].

PubMed

Grandpierre, R; Chatelier, G

1968-01-01

Psychomotor reactions have been studied in Nemestrina Macaques during flights in rockets in which there were periods of weightlessness lasting about 10 minutes. The animals had undergone motor conditioning and responded to a light signal by pressing on a button placed on a panel where there were four other undifferentiated buttons. The lighting of the panel and pressing on the different buttons in reply was recorded with respect to time. Movement was observed by film recording, and electrical activity of the brain was kept under observation by six different recordings of the cortex. Activity of stretching and bending muscles of the legs was recorded, as well as breathing, and heart activity was recorded on an electrocardiogram. These psychological parameters were transmitted to the earth by long-distance measurement during the entire flight. The recordings made it possible to confirm that the absence of the sensation of weight seems to reduce the alertness of the animals. This fact had already been observed in Wistar's rat and cat. The sensor-psychomotor responses undergo important individual variations and depend on the motivation of the subjects. A very well motivated one reacted after a short period of adaption, as it did in the laboratory: one that was much less motivated would not work until after weightlessness has ended, and showed signs of drowsiness. These observations made during the flights in rockets confirm those of Chambers et al., Harris et al., Lilly et al. made in immersion studies; they show the important role of weight in maintaining alertness, but that changes of psychomotor activity are particularly related to motivation.

Estimating Drug Costs: How do Manufacturer Net Prices Compare with Other Common US Price References?

PubMed

Mattingly, T Joseph; Levy, Joseph F; Slejko, Julia F; Onwudiwe, Nneka C; Perfetto, Eleanor M

2018-05-12

Drug costs are frequently estimated in economic analyses using wholesale acquisition cost (WAC), but what is the best approach to develop these estimates? Pharmaceutical manufacturers recently released transparency reports disclosing net price increases after accounting for rebates and other discounts. Our objective was to determine whether manufacturer net prices (MNPs) could approximate the discounted prices observed by the U.S. Department of Veterans Affairs (VA). We compared the annual, average price discounts voluntarily reported by three pharmaceutical manufacturers with the VA price for specific products from each company. The top 10 drugs by total sales reported from company tax filings for 2016 were included. The discount observed by the VA was determined from each drug's list price, reported as WAC, in 2016. Descriptive statistics were calculated for the VA discount observed and a weighted price index was calculated using the lowest price to the VA (Weighted VA Index), which was compared with the manufacturer index. The discounted price as a percentage of the WAC ranged from 9 to 74%. All three indexes estimated by the average discount to the VA were at or below the manufacturer indexes (42 vs. 50% for Eli Lilly, 56 vs. 65% for Johnson & Johnson, and 59 vs. 59% for Merck). Manufacturer-reported average net prices may provide a close approximation of the average discounted price granted to the VA, suggesting they may be a useful proxy for the true pharmacy benefits manager (PBM) or payer cost. However, individual discounts for products have wide variation, making a standard discount adjustment across multiple products less acceptable.

Must Star-forming Galaxies Rapidly Get Denser before They Quench?

NASA Astrophysics Data System (ADS)

Abramson, L. E.; Morishita, T.

2018-05-01

Using the deepest data yet obtained, we find no evidence preferring compaction-triggered quenching—where rapid increases in galaxy density truncate star formation—over a null hypothesis in which galaxies age at constant surface density ({{{Σ }}}e\\equiv {M}* /2π {r}e2). Results from two fully empirical analyses and one quenching-free model calculation support this claim at all z ≤ 3: (1) qualitatively, galaxies’ mean U–V colors at 6.5 ≲ {log}{{{Σ }}}e/{\\text{}}{M}ȯ {kpc}}-2≲ 10 have reddened at rates/times correlated with {{{Σ }}}e, implying that there is no density threshold at which galaxies turn red but that {{{Σ }}}e sets the pace of maturation; (2) quantitatively, the abundance of {log}{M}* /{\\text{}}{M}ȯ ≥slant 9.4 red galaxies never exceeds that of the total population a quenching time earlier at any {{{Σ }}}e, implying that galaxies need not transit from low to high densities before quenching; (3) applying d{log}{r}e/{dt}=1/2 d{log}{M}* /{dt} to a suite of lognormal star formation histories reproduces the evolution of the size–mass relation at {log}{M}* /{\\text{}}{M}ȯ ≥slant 10. All results are consistent with evolutionary rates being set ab initio by global densities, with denser objects evolving faster than less-dense ones toward a terminal quiescence induced by gas depletion or other ∼Hubble-timescale phenomena. Unless stellar ages demand otherwise, observed {{{Σ }}}e thresholds need not bear any physical relation to quenching beyond this intrinsic density–formation epoch correlation, adding to Lilly & Carollo’s arguments to that effect.

Reconnaissance studies of potential petroleum source rocks in the Middle Jurassic Tuxedni Group near Red Glacier, eastern slope of Iliamna Volcano

USGS Publications Warehouse

Stanley, Richard G.; Herriott, Trystan M.; LePain, David L.; Helmold, Kenneth P.; Peterson, C. Shaun

2013-01-01

Previous geological and organic geochemical studies have concluded that organic-rich marine shale in the Middle Jurassic Tuxedni Group is the principal source rock of oil and associated gas in Cook Inlet (Magoon and Anders, 1992; Magoon, 1994; Lillis and Stanley, 2011; LePain and others, 2012; LePain and others, submitted). During May 2009 helicopter-assisted field studies, 19 samples of dark-colored, fine-grained rocks were collected from exposures of the Red Glacier Formation of the Tuxedni Group near Red Glacier, about 70 km west of Ninilchik on the eastern flank of Iliamna Volcano (figs. 1 and 3). The rock samples were submitted to a commercial laboratory for analysis by Rock-Eval pyrolysis and to the U.S. Geological Survey organic geochemical laboratory in Denver, Colorado, for analysis of vitrinite reflectance. The results show that values of vitrinite reflectance (percent Ro) in our samples average about 2 percent, much higher than the oil window range of 0.6–1.3 percent (Johnsson and others, 1993). The high vitrinite reflectance values indicate that the rock samples experienced significant heating and furthermore suggest that these rocks may have generated oil and gas in the past but no longer have any hydrocarbon source potential. The high thermal maturity of the rock samples may have resulted from (1) the thermaleffects of igneous activity (including intrusion by igneous rocks), (2) deep burial beneath Jurassic, Cretaceous, and Tertiary strata that were subsequently removed by uplift and erosion, or (3) the combined effects of igneous activity and burial.

Injection Force of SoloSTAR® Compared with Other Disposable Insulin Pen Devices at Constant Volume Flow Rates

PubMed Central

van der Burg, Thomas

2011-01-01

Background Injection force is a particularly important practical aspect of therapy for patients with diabetes, especially those who have dexterity problems. This laboratory-based study compared the injection force of the SoloSTAR® insulin pen (SoloSTAR; sanofi-aventis) versus other available disposable pens at injection speeds based on the delivered volume of insulin released at the needle. Method Four different prefilled disposable pens were tested: SoloSTAR containing insulin glargine; FlexPen® and the Next Generation FlexPen® (NGFP) (Novo Nordisk), both containing insulin detemir; and KwikPen® containing insulin lispro (Eli Lilly). All pens were investigated using the maximum dispense volume for each pen type [80 units (U) for SoloSTAR; 60 U for the other pens], from the free needle tip dispensing into a beaker. Twenty pens of each type were fitted with the recommended needles and tested at two dose speeds (6 and 10 U/s); each pen was tested twice. Results Mean plateau injection force and maximum injection force were consistently lower with SoloSTAR compared with FlexPen, NGFP, and KwikPen at both injection speeds tested. An injection speed of 10 U/s was associated with higher injection force compared with 6 U/s for all the pens tested (p < .001). Conclusions SoloSTAR stands out because of its low injection force, even when compared with newer insulin pen devices such as the KwikPen and NGFP. This may enable patients, especially those with dexterity problems, to administer insulin more easily and improve management of their diabetes. PMID:21303637

Treatment patterns and health care resource use in patients receiving multiple lines of therapy for metastatic squamous cell carcinoma of the head and neck in the United Kingdom.

PubMed

La, Elizabeth M; Smyth, Emily Nash; Talbird, Sandra E; Li, Li; Kaye, James A; Lin, Aimee Bence; Bowman, Lee

2018-06-21

This study evaluated the patterns of care and health care resource use (HCRU) in patients with metastatic squamous cell carcinoma of the head and neck (SCCHN) who received ≥3 lines of systemic therapy in the United Kingdom (UK). Oncologists (n = 40) abstracted medical records for patients with metastatic SCCHN who initiated third-line systemic therapy during 1 January 2011-30 August 2014 (n = 220). Patient characteristics, treatment patterns and SCCHN-related HCRU were summarised descriptively for the metastatic period; exploratory multivariable regression analyses were conducted on select HCRU outcomes. At metastatic diagnosis, most patients had an Eastern Cooperative Oncology Group performance status (PS) of 0/1 (95%). For patients with PS 0/1, the most common first-line treatment was cisplatin+5-fluorouracil (5-FU); docetaxel was the most common second- and third-line treatment. For patients with PS ≥ 2, the most common first-, second-, and third-line treatments were carboplatin+5-FU, cetuximab, and methotrexate, respectively. Most patients received supportive care during (85%) and after (89%) therapy. This study provides useful information, prior to the availability of immunotherapy, on patient characteristics, treatment patterns, HCRU, and survival in a real-world UK population with metastatic SCCHN receiving ≥3 lines of systemic therapy. Patterns of care and HCRU varied among patients with metastatic SCCHN; specific systemic therapies varied by patient PS. © 2018 Eli Lilly and Company. European Journal of Cancer Care published by John Wiley & Sons Ltd.

Regulation of Episodic Growth Hormone Secretion by the Central Epinephrine System

PubMed Central

Terry, L. Cass; Crowley, W. R.; Johnson, M. D.

1982-01-01

Catecholamines are postulated to regulate growth hormone (GH) secretion by their influence on the release of two hypothalamic substances, somatostatin, which inhibits GH release, and GH-releasing factor, as yet unidentified. Extensive pharmacologic studies in man and animals indicate a stimulatory effect of central norepinephrine and dopamine on GH, but the function of epiphephrine (EPI) is uncertain. Furthermore, many of the agents used to study the role of catecholamines in GH regulation are not selective in that they affect adrenergic as well as nor-adrenergic and/or dopaminergic neurotransmission. In the present investigation, central nervous system (CNS) EPI biosynthesis was selectively interrupted with the specific norepinephrine N-methyltransferase inhibitors, SK & F 64139 (Smith, Kline & French Laboratories) and LY 78335, (Eli Lilly & Co. Research Laboratories) and the effects of central EPI depletion on episodic GH secretion in the chronically cannulated rat model were determined. Inhibition of CNS EPI synthesis with SK & F 64139 caused complete suppression of episodic GH secretion and concomitantly reduced the EPI level in the hypothalamus without affecting dopamine or norepinephrine. Administration of LY 78335 produced similar effects on pulsatile GH. Morphine-induced, but not clonidine-induced, GH release also was blocked by SK & F 64139. These results indicate that (a) the central EPI system has a major stimulatory function in episodic GH release, (b) morphine-induced GH release is mediated by the central EPI system, and (c) clonidine stimulates GH release by activation of postsynaptic α-adrenergic receptors. Drugs that affect CNS adrenergic systems have a potential role in the diagnosis and treatment of disorders of GH secretion. PMID:7054231

The second Lilly Prize Lecture, University of Newcastle, July 1977. beta-Adrenergic receptor blockade in hypertension, past, present and future.

PubMed Central

Prichard, B N

1978-01-01

All beta-adrenoceptor blocking drugs that have been described share the common property of being competitive inhibitors. They differ in their associated properties, the presence or absence of cardioselectivity, membrane stabilizing activity, and partial agonist activity. Recently some beta-adrenoceptor blocking drugs have been reported which also possess alpha-adrenoceptor blocking activity. The associated properties have been used as a basis for classifying beta-adrenoceptor blocking drugs (Fitzgerald, 1969, 1972). The presence or absence of cardioselectivity is most useful for dividing beta-adrenoceptor blocking drugs. The non-selective drugs (Division I) can be further divided according to the presence or absence of intrinsic sympathomimetic activity (ISA) and membrane stabilizing activity (Fitzgerald's groups I-IV). Group I possess both membrane activity and ISA, e.g. alprenolol, oxprenolol, group II just membrane action, e.g. propanolol, group III ISA but no membrane action, e.g. pindolol. Fitzgerald placed pindolol in group I but should be placed in group III as it possesses a high degree of beta-adrenoceptor blocking potency in relation to its membrane activity (Prichard, 1974). Finally drugs in group IV have neither ISA nor membrane action, e.g. sotalol, timolol. The cardioselective drugs (Division II) can be similarly sub-divided into groups I-IV according to the presence or absence of ISA or membrane action (Fitzgerald grouped all these together as group V). Lastly there are new beta-adrenergic receptor blocking drugs which in addition have alpha- adrenergic receptor blocking properties (Division III). PMID:26370

Predictors of Change in Adherence Status from 1 Year to the Next Among Patients with Type 2 Diabetes Mellitus on Oral Antidiabetes Drugs.

PubMed

Saundankar, Vishal; Peng, Xiaomei; Fu, Haoda; Ascher-Svanum, Haya; Rodriguez, Angel; Ali, Ayad; Slabaugh, Lane; Young, Peinie; Louder, Anthony

2016-05-01

Diabetes is a leading cause of morbidity, mortality, and medical resource utilization in the United States and worldwide. Treatment is aimed at keeping blood glucose levels close to normal and preventing or delaying medical complications. It has been estimated that only 50% of patients with diabetes in the United States achieve glycosylated hemoglobin A1c level < 7%. Nonadherence to antidiabetic medications has been identified as a major factor related to poor glycemic control. To (a) assess adult patients with type 2 diabetes mellitus (T2DM) whose adherence status to oral antidiabetic drugs (OADs) changed from 1 year to the next and (b) identify predictors of change in adherence status. This retrospective study of the Humana Medicare Advantage Database included patients with T2DM and continuous enrollment between 2010 and 2012. Proportion of days covered (PDC) by OADs was calculated for each of the 3 study years (2010, 2011, 2012). Patients were classified as adherent (PDC ≥ 80%) or nonadherent (PDC < 80%) during each year. Patient characteristics from the baseline period (2010) were used as covariates, and adherence status changes from baseline to follow-up year (2011) were used as response variables. Data from the subsequent study periods (2011 as baseline, 2012 as follow-up) were used to validate the model (final model). A total of 238,402 patients met inclusion criteria. Among them, 144,216 (60.5%) were adherent, and 94,186 (39.5%) were nonadherent during the baseline period. Change in adherence status from baseline to follow-up year was observed in 31,320 (21.7%) patients that were adherent and 39,284 (41.7%) patients that were nonadherent during the baseline year. The final model for baseline adherent patients had a receiver-operating characteristic (ROC) index of 73% and a misclassification rate of 39%. The predictors of highest importance were identified as total number of prescriptions filled with 90-day supply, diabetes-related pill burden, longest gap in OADs, total number of antidiabetic classes filled, and copay for the last OAD filled. The final model had a sensitivity value of 76.4%. The final model for baseline nonadherent patients had a ROC index of 68%, a misclassification rate of 36.4%, and sensitivity value of 52.9%. The predictors of highest importance were diabetes-related pill burden, longest gap in OADs, month-wise patient oscillation from adherent to nonadherent during baseline year, total number of prescriptions filled with a 90-day supply, and total pill burden during the baseline year. One third of the T2DM patients changed adherence status from 1 year to the next, and factors associated with adherence status changes were identified. Predictive models such as those used in this study can serve as useful and cost-effective tools for payers, helping to identify members that should be targeted for adherence enhancement programs and, ultimately, to improve patients' long-term outcomes. Funding for this research was provided by Eli Lilly and Company. Comprehensive Health Insights, owned by Humana, completed this study. Peng, Fu, Ascher-Svanum, Ali, and Rodriguez are employees of Eli Lilly and Company. Saundankar and Louder are employed by Comprehensive Health Insights, and Slabaugh and Young are employed by Humana. Study concept and design were contributed by Peng, Ascher-Svanum, and Young. Saundankar and Louder took the lead in data collection, while Saundankar, Peng, Fu, and Louder interpreted the data. The manuscript was written by Saundankar, Peng, Fu, and Louder and revised by Saundankar, Rodriguez, Ali, and Louder.

Interventions to treat premature ejaculation: a systematic review short report.

PubMed

Cooper, Katy; Martyn-St James, Marrissa; Kaltenthaler, Eva; Dickinson, Kath; Cantrell, Anna

2015-03-01

Premature ejaculation (PE) is commonly defined as ejaculation with minimal sexual stimulation before, on or shortly after penetration and before the person wishes it. PE can be either lifelong and present since first sexual experiences (primary), or acquired (secondary), beginning later (Godpodinoff ML. Premature ejaculation: clinical subgroups and etiology. J Sex Marital Ther 1989;15:130-4). Treatments include behavioural and pharmacological interventions. To systematically review evidence for clinical effectiveness of behavioural, topical and systemic treatments for PE. The following databases were searched from inception to 6 August 2013 for published and unpublished research evidence: MEDLINE; EMBASE; Cumulative Index to Nursing and Allied Health Literature; The Cochrane Library including the Cochrane Systematic Reviews Database, Cochrane Controlled Trials Register, Database of Abstracts of Reviews of Effects and the Health Technology Assessment database; ISI Web of Science, including Science Citation Index, and the Conference Proceedings Citation Index-Science. The US Food and Drug Administration website and the European Medicines Agency (EMA) website were also searched. Randomised controlled trials (RCTs) in adult men with PE were eligible (or non-RCTs in the absence of RCTs). RCT data were extrapolated from review articles when available. The primary outcome was intravaginal ejaculatory latency time (IELT). Data were meta-analysed when possible. Other outcomes included sexual satisfaction, control over ejaculation, relationship satisfaction, self-esteem, quality of life, treatment acceptability and adverse events (AEs). A total of 103 studies (102 RCTs, 65 from reviews) were included. RCTs were available for all interventions except yoga. The following interventions demonstrated significant improvements (p < 0.05) in arithmetic mean difference in IELT compared with placebo: topical anaesthetics - eutectic mixture of local anaesthetics (EMLA(®), AstraZeneca), topical eutectic mixture for PE (Plethora Solutions Ltd) spray; selective serotonin reuptake inhibitors (SSRIs) - citalopram (Cipramil(®), Lundbeck), escitalopram (Cipralex(®), Lundbeck), fluoxetine, paroxetine, sertraline, dapoxetine (Priligy(®), Menarini), 30 mg or 60 mg; serotonin-noradrenaline reuptake inhibitors - duloxetine (Cymbalta(®), Eli Lilly & Co Ltd); tricyclic antidepressants - inhaled clomipramine 4 mg; phosphodiesterase-5 (PDE5) inhibitors - vardenafil (Levitra(®), Bayer), tadalafil (Cialis(®), Eli Lilly & Co Ltd); opioid analgesics - tramadol (Zydol SR(®), Grünenthal). Improvements in sexual satisfaction and other outcomes compared with placebo were evident for SSRIs, PDE5 inhibitors and tramadol. Outcomes for interventions not compared with placebo were as follows: behavioural therapies - improvements over wait list control in IELT and other outcomes, behavioural therapy plus pharmacotherapy better than either therapy alone; alpha blockers - terazosin (Hytrin(®), AMCO) not significantly different to antidepressants in ejaculation control; acupuncture - improvements over sham acupuncture in IELT, conflicting results for comparisons with SSRIs; Chinese medicine - improvements over treatment as usual; delay device - improvements in IELT when added to stop-start technique; yoga - improved IELT over baseline, fluoxetine better than yoga. Treatment-related AEs were evident with most pharmacological interventions. Although data extraction from reviews was optimised when more than one review reported data for the same RCT, the reliability of the data extraction within these reviews cannot be guaranteed by this assessment report. Several interventions significantly improved IELT. Many interventions also improved sexual satisfaction and other outcomes. However, assessment of longer-term safety and effectiveness is required to evaluate whether or not initial treatment effects are maintained long term, whether or not dose escalation is required, how soon treatment effects end following treatment cessation and whether or not treatments can be stopped and resumed at a later time. In addition, assessment of the AEs associated with long-term treatment and whether or not different doses have differing AE profiles is required. This study is registered as PROSPERO CRD42013005289. The National Institute for Health Research Health Technology Assessment programme.

A Single Dose, Randomized, Controlled Proof-Of-Mechanism Study of a Novel Vasopressin 1a Receptor Antagonist (RG7713) in High-Functioning Adults with Autism Spectrum Disorder

PubMed Central

Umbricht, Daniel; del Valle Rubido, Marta; Hollander, Eric; McCracken, James T; Shic, Frederick; Scahill, Lawrence; Noeldeke, Jana; Boak, Lauren; Khwaja, Omar; Squassante, Lisa; Grundschober, Christophe; Kletzl, Heidemarie; Fontoura, Paulo

2017-01-01

The core symptoms of autism spectrum disorder (ASD) include impaired social communication, repetitive behaviors, and restricted interests. No effective pharmacotherapy for these core deficits exists. Within the domain of social communication, the vasopressin system is implicated in social cognition and social signaling deficits of ASD, and represents a potential therapeutic target. We assessed the effects of a single 20 mg intravenous dose of the arginine vasopressin receptor 1A (V1a) antagonist, RG7713, on exploratory biomarkers (eye tracking), behavioral and clinical measures of social cognition and communication (affective speech recognition (ASR), reading the mind in the eyes, olfactory identification, scripted interaction), and safety and tolerability in a multicenter, randomized, double-blind, placebo-controlled, cross-over study of 19 high-functioning adult male subjects with DSM-IV Autistic Disorder (age 18–45 years; full scale IQ >70; ABC-Irritability subscale ⩽13). Eye-tracking showed an increase in biological motion orienting preference with RG7713 (ES=0.8, p=0.047) and a non-significant improvement in the composite score (ES=0.2, p=0.29). RG7713 reduced ability to detect lust (ES=−0.8, p=0.03) and fear (ES=−0.7, p=0.07) in ASR. However, when all eight individual emotion subscales were combined into an overall ASR performance score, the reduction was non-significant (ES=−0.1, p=0.59). Thirteen adverse events were reported in 10 subjects; all were of mild (11/13) or moderate (2/13) severity. Although interpretation should be cautious due to multiple comparisons and small sample size, these results provide preliminary evidence from experimental and behavioral biomarkers, that blockade of the V1a receptor may improve social communication in adults with high-functioning ASD. ClinicalTrials.gov identifier: NCT01474278 A Study of RO5028442 in Adult Male High-Functioning Autistic Patients. Available at: https://clinicaltrials.gov/ct2/show/NCT01474278 PMID:27711048

Gene surfing in expanding populations.

PubMed

Hallatschek, Oskar; Nelson, David R

2008-02-01

Large scale genomic surveys are partly motivated by the idea that the neutral genetic variation of a population may be used to reconstruct its migration history. However, our ability to trace back the colonization pathways of a species from their genetic footprints is limited by our understanding of the genetic consequences of a range expansion. Here, we study, by means of simulations and analytical methods, the neutral dynamics of gene frequencies in an asexual population undergoing a continual range expansion in one dimension. During such a colonization period, lineages can fix at the wave front by means of a "surfing" mechanism [Edmonds, C.A., Lillie, A.S., Cavalli-Sforza, L.L., 2004. Mutations arising in the wave front of an expanding population. Proc. Natl. Acad. Sci. 101, 975-979]. We quantify this phenomenon in terms of (i) the spatial distribution of lineages that reach fixation and, closely related, (ii) the continual loss of genetic diversity (heterozygosity) at the wave front, characterizing the approach to fixation. Our stochastic simulations show that an effective population size can be assigned to the wave that controls the (observable) gradient in heterozygosity left behind the colonization process. This effective population size is markedly higher in the presence of cooperation between individuals ("pushed waves") than when individuals proliferate independently ("pulled waves"), and increases only sub-linearly with deme size. To explain these and other findings, we develop a versatile analytical approach, based on the physics of reaction-diffusion systems, that yields simple predictions for any deterministic population dynamics. Our analytical theory compares well with the simulation results for pushed waves, but is less accurate in the case of pulled waves when stochastic fluctuations in the tip of the wave are important.

Beyond the Quantum Hall Effect: New Phases of 2D Electrons at High Magnetic Field

NASA Astrophysics Data System (ADS)

Eisenstein, James

2007-03-01

In this talk I will discuss recent experiments on high mobility single and double layer 2D electron systems in which collective phases lying outside the usual quantum Hall effect paradigm have been detected and studied. For example, in single layer 2D systems near half-filling of highly excited Landau levels new states characterized by a massive anisotropy in the electrical resistivity of the sample are observed at very low temperature. The anisotropy has been widely interpreted as the signature of a new class of correlated electron phases which incorporate a stripe-like charge density modulation. Orientational ordering of small striped domains at low temperatures accounts for the resistive anisotropy and is reminiscent of the isotropic-to-nematic phase transition in classical liquid crystals. Double layer 2D electron systems possess collective phases not present in single layer systems. In particular, when the total number of electrons in the bilayer equals the degeneracy of a single Landau level, an unusual phase appears at small layer separation. This phase possesses a novel broken symmetry, spontaneous interlayer phase coherence, which has a number of dramatic experimental signatures. The interlayer tunneling conductance develops a strong and very sharp resonance around zero bias resembling the dc Josephson effect. At the same time, both the longitudinal and Hall resistances of the sample vanish at low temperatures when currents are driven in opposite directions through the two layers. These, and other observations are broadly consistent with theories in which the broken symmetry phase can equivalently be described as a pseudospin ferromagnet or an (imperfect) excitonic superfluid. This work reflects a collaboration with M.P. Lilly, K.B. Cooper, I.B. Spielman, M. Kellogg, L.A. Tracy, L.N. Pfeiffer, and K.W. West.

FIRST LEGO League Kickoff

NASA Technical Reports Server (NTRS)

2007-01-01

Randall Hicks (right), Jacobs Technology's Education Services manager at NASA John C. Stennis Space Center, answers questions about the playing field for FIRST (For Inspiration and Recognition of Science and Technology) LEGO League's 2007 Challenge, `Power Puzzle.' More than 140 teachers, mentors, parents and students from 15 schools attended the Sept. 15 FLL season kickoff at StenniSphere, the visitor center at SSC. The teams from southern and central Mississippi and Mobile, Ala., who came to SSC heard rules for and asked questions about `Power Puzzle,' and saw robot demonstrations by Gulfport and Picayune high schools' past FIRST Robotics competitions. Using LEGO Mindstorms NXT kits, FLL teams of children ages 9-14 will spend the next three months building and programming robots to perform 'Power Puzzle's' challenge tasks, then pit them in competitions. They also will submit a research project about how energy choices impact the environment and the economy. The season will culminate at the Mississippi Championship Tournament on Dec. 8 at the Mississippi Gulf Coast Community College. FLL, considered the `little league' of the FIRST Robotics Competition, partners FIRST and the LEGO Group. Competitions aim to inspire and celebrate science and technology using real-world context and hands-on experimentation. NASA recognizes FIRST activities as an excellent hands-on method to increase student knowledge of science, engineering, technology and mathematics. Schools represented in this year's kickoff were: Madison Avenue Upper Elementary, the Mississippi Band of Choctaw Indians' Conehatta Elementary, Hattiesburg's Lillie Burney Elementary, Pearl Upper Elementary, Long Beach Middle, Oktibehha Elementary, d'Iberville Middle, Saucier's West Wortham Middle, Picayune's Nicholson Elementary and Roseland Park Baptist Church Academy, Bay St. Louis' St. Stanislaus College and Mobile's Davidson High, as well as two home-school groups from the Jackson area.

Covariates of depression and high utilizers of healthcare: Impact on resource use and costs.

PubMed

Robinson, Rebecca L; Grabner, Michael; Palli, Swetha Rao; Faries, Douglas; Stephenson, Judith J

2016-06-01

To characterize healthcare costs, resource use, and treatment patterns of survey respondents with a history of depression who are high utilizers (HUds) of healthcare and to identify factors associated with high utilization. Adults with two or more depression diagnoses identified from the HealthCore Integrated Research Database were invited to participate in the CODE study, which links survey data with 12-month retrospective claims data. Patient surveys provided data on demographics, general health, and symptoms and/or comorbidities associated with depression. Similar clinical conditions also were identified from the medical claims. Factors associated with high utilization were identified using logistic regression models. Of 3132 survey respondents, 1921 were included, 193 of whom were HUds (defined as those who incurred the top 10% of total all-cause costs in the preceding 12months). Mean total annual healthcare costs were eightfold greater for HUds than for non-HUds ($US56,145 vs. $US6,954; p<.0001). HUds incurred more inpatient encounters (p<.0001) and emergency department (p=.01) and physician office visits (p<.0001). Similar findings were observed for mental healthcare costs/resource use. HUds were prescribed twice as many medications (total mean: 16.86 vs. 8.32; psychotropic mean: 4.11 vs. 2.61; both p<.0001). HUds reported higher levels of depression severity, fatigue, sleep difficulties, pain, high alcohol consumption, and anxiety. Predictors of becoming a HUd included substance use, obesity, cardiovascular disease, comorbidity severity, psychiatric conditions other than depression, and pain. Focusing on pain, substance use, and psychiatric conditions beyond depression may be effective approaches to reducing high costs in patients with depression. Copyright © 2016 Eli Lilly and Company. Published by Elsevier Inc. All rights reserved.

The effects of atomoxetine on emotional control in adults with ADHD: An integrated analysis of multicenter studies.

PubMed

Asherson, P; Stes, S; Nilsson Markhed, M; Berggren, L; Svanborg, P; Kutzelnigg, A; Deberdt, W

2015-06-01

To investigate the effects of atomoxetine on emotional control in adults with ADHD. We performed an integrated analysis using individual patient data pooled from three Eli Lilly-sponsored studies. An integrated analysis can be viewed as a meta-analysis of individual patient-level data, rather than study-level summary data. Two populations were identified: a large sample of patients with pre-treatment baseline data (the "overall population"; n=2846); and a subset of these patients with placebo-controlled efficacy data from baseline to 10 or 12 weeks after initiating treatment (the "placebo-controlled population"; n=829). At baseline, in the overall population, ∼50% of ADHD patients had BRIEF-AS (Behavior Rating Inventory of Executive Function-Adult Version Self-Report) Emotional control subscores between 21 and 30, compared with ∼10% of normative subjects in the BRIEF-A manual. At endpoint, in the placebo-controlled population, atomoxetine led to a small (effect size 0.19) but significant (P=0.013) treatment effect for emotional control. The effect size was 0.32 in patients with BRIEF-AS Emotional control scores>20 at baseline. Improvements in emotional control correlated with improvements in the core ADHD symptoms and quality-of-life. As deficient emotional control is associated with impaired social, educational and occupational functioning over and above that explained by core ADHD symptoms alone, improvements in emotional control may be clinically relevant. At baseline, adults with ADHD were more likely to have impaired emotional control than normative subjects. In the adult ADHD patients, atomoxetine treatment was associated with improvements in emotional control, as well as in core ADHD symptoms and quality-of-life. Copyright © 2015. Published by Elsevier Masson SAS.

Cost Analyses in the US and Japan: A Cross-Country Comparative Analysis Applied to the PRONOUNCE Trial in Non-Squamous Non-Small Cell Lung Cancer.

PubMed

Hess, Lisa M; Rajan, Narayan; Winfree, Katherine; Davey, Peter; Ball, Mark; Knox, Hediyyih; Graham, Christopher

2015-12-01

Health technology assessment is not required for regulatory submission or approval in either the United States (US) or Japan. This study was designed as a cross-country evaluation of cost analyses conducted in the US and Japan based on the PRONOUNCE phase III lung cancer trial, which compared pemetrexed plus carboplatin followed by pemetrexed (PemC) versus paclitaxel plus carboplatin plus bevacizumab followed by bevacizumab (PCB). Two cost analyses were conducted in accordance with International Society For Pharmacoeconomics and Outcomes Research good research practice standards. Costs were obtained based on local pricing structures; outcomes were considered equivalent based on the PRONOUNCE trial results. Other inputs were included from the trial data (e.g., toxicity rates) or from local practice sources (e.g., toxicity management). The models were compared across key input and transferability factors. Despite differences in local input data, both models demonstrated a similar direction, with the cost of PemC being consistently lower than the cost of PCB. The variation in individual input parameters did affect some of the specific categories, such as toxicity, and impacted sensitivity analyses, with the cost differential between comparators being greater in Japan than in the US. When economic models are based on clinical trial data, many inputs and outcomes are held consistent. The alterable inputs were not in and of themselves large enough to significantly impact the results between countries, which were directionally consistent with greater variation seen in sensitivity analyses. The factors that vary across jurisdictions, even when minor, can have an impact on trial-based economic analyses. Eli Lilly and Company.

Some NACA Muroc personnel with snowman

NASA Technical Reports Server (NTRS)

1949-01-01

The late 1940s saw increased flight activity, and more women computers were needed at the NACA Muroc Flight Test Unit than the ones who had originally arrived in 1946. A call went out to the NACA Langley, Lewis, and Ames laboratories for more women computers. Pictured in this photograph with the Snowman are some of the women computers who responded to the call for help in 1948 along with Roxanah, Emily, Dorothy, who were already here. Standing left to right: Mary (Tut) Hedgepeth, from Langley; Lilly Ann Bajus, Lewis; Roxanah Yancey, Emily Stephens, Jane Collons (Procurement), Leona Corbett (Personnel), Angel Dunn, Langley. Kneeling left to right: Dorothy (Dottie) Crawford Roth, Lewis; Dorothy Clift Hughes, and Gertrude (Trudy) Wilken Valentine, Lewis. In National Advisory Committee for Aeronautics (NACA) terminology of 1946, computers were employees who performed laborious and time-consuming mathematical calculations and data reduction from long strips of records generated by onboard aircraft instrumentation. Virtually without exception, computers were female; at least part of the rationale seems to have been the notion that the work was long and tedious, and men were not thought to have the patience to do it. Though equipment changed over the years and most computers eventually found themselves programming and operating electronic computers, as well as doing other data processing tasks, being a computer initially meant long hours with a slide rule, hunched over illuminated light boxes measuring line traces from grainy and obscure strips of oscillograph film. Computers suffered terrible eyestrain, and those who didn't begin by wearing glasses did so after a few years. But they were initially essential employees at the Muroc Flight Test Unit and NACA High-Speed Flight Research Station, taking the oscillograph flight records and 'reducing' the data on them to make them useful to research engineers, who analyzed the data.

Impact of patient selection and study characteristics on signal detection in placebo-controlled trials with antidepressants.

PubMed

Mancini, Michele; Wade, Alan G; Perugi, Giulio; Lenox-Smith, Alan; Schacht, Alexander

2014-04-01

An increasing rate of antidepressant trials fail due to large placebo responses. This analysis aimed to identify variables influencing signal detection in clinical trials of major depressive disorder. Patient-level data of randomized patients with a duloxetine dose ≥ 60 mg/day were obtained from Lilly. Total scores of the Hamilton Depression Rating scale (HAM-D) were used as efficacy endpoints. In total, 4661 patients from 14 studies were included in the analysis. The overall effect size (ES), based on the HAM-D total score at endpoint, between duloxetine and placebo was -0.272. Although no statistically significant interactions were found, the following results for factors influencing ES were seen: a very low ES (-0.157) in patients in the lowest baseline HAM-D category and in patients recruited in the last category of the recruitment period (-0.122). A higher ES in patients recruited in centers with a site-size at but not more than 2.5 times the average site-size for the study (-0.345). Study characteristics that resulted in low signal detection in our database were: <80% study completers, a HAM-D placebo response >5 points, a high variability of placebo response (SD > 7 points HAM-D), >6 post baseline visits per study, and use of an active control drug. Simpler trial designs, more homogeneous and mid-sized study sites, a primary analysis based on a higher cutoff blinded to investigators to avoid the influence of score inflation in mild patients and, if possible, studies without an active control group could lead to a better signal detection of antidepressive efficacy. Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.

Evaluation of subgrid-scale models in large-eddy simulations of turbulent flow in a centrifugal pump impeller

NASA Astrophysics Data System (ADS)

Yang, Zhengjun; Wang, Fujun; Zhou, Peijian

2012-09-01

The current research of large eddy simulation (LES) of turbulent flow in pumps mainly concentrates in applying conventional subgrid-scale (SGS) model to simulate turbulent flow, which aims at obtaining the flow field in pump. The selection of SGS model is usually not considered seriously, so the accuracy and efficiency of the simulation cannot be ensured. Three SGS models including Smagorinsky-Lilly model, dynamic Smagorinsky model and dynamic mixed model are comparably studied by using the commercial CFD code Fluent combined with its user define function. The simulations are performed for the turbulent flow in a centrifugal pump impeller. The simulation results indicate that the mean flows predicted by the three SGS models agree well with the experimental data obtained from the test that detailed measurements of the flow inside the rotating passages of a six-bladed shrouded centrifugal pump impeller performed using particle image velocimetry (PIV) and laser Doppler velocimetry (LDV). The comparable results show that dynamic mixed model gives the most accurate results for mean flow in the centrifugal pump impeller. The SGS stress of dynamic mixed model is decompose into the scale similar part and the eddy viscous part. The scale similar part of SGS stress plays a significant role in high curvature regions, such as the leading edge and training edge of pump blade. It is also found that the dynamic mixed model is more adaptive to compute turbulence in the pump impeller. The research results presented is useful to improve the computational accuracy and efficiency of LES for centrifugal pumps, and provide important reference for carrying out simulation in similar fluid machineries.

FIRST LEGO League Kickoff

NASA Image and Video Library

2007-09-15

Randall Hicks (right), Jacobs Technology's Education Services manager at NASA John C. Stennis Space Center, answers questions about the playing field for FIRST (For Inspiration and Recognition of Science and Technology) LEGO League's 2007 Challenge, `Power Puzzle.' More than 140 teachers, mentors, parents and students from 15 schools attended the Sept. 15 FLL season kickoff at StenniSphere, the visitor center at SSC. The teams from southern and central Mississippi and Mobile, Ala., who came to SSC heard rules for and asked questions about `Power Puzzle,' and saw robot demonstrations by Gulfport and Picayune high schools' past FIRST Robotics competitions. Using LEGO Mindstorms NXT kits, FLL teams of children ages 9-14 will spend the next three months building and programming robots to perform 'Power Puzzle's' challenge tasks, then pit them in competitions. They also will submit a research project about how energy choices impact the environment and the economy. The season will culminate at the Mississippi Championship Tournament on Dec. 8 at the Mississippi Gulf Coast Community College. FLL, considered the `little league' of the FIRST Robotics Competition, partners FIRST and the LEGO Group. Competitions aim to inspire and celebrate science and technology using real-world context and hands-on experimentation. NASA recognizes FIRST activities as an excellent hands-on method to increase student knowledge of science, engineering, technology and mathematics. Schools represented in this year's kickoff were: Madison Avenue Upper Elementary, the Mississippi Band of Choctaw Indians' Conehatta Elementary, Hattiesburg's Lillie Burney Elementary, Pearl Upper Elementary, Long Beach Middle, Oktibehha Elementary, d'Iberville Middle, Saucier's West Wortham Middle, Picayune's Nicholson Elementary and Roseland Park Baptist Church Academy, Bay St. Louis' St. Stanislaus College and Mobile's Davidson High, as well as two home-school groups from the Jackson area.

Combined treatment with pemetrexed and vinflunine in patients with metastatic urothelial cell carcinoma after prior platinum-containing chemotherapy - results of an exploratory phase I study.

PubMed

Pappot, H; von der Maase, H; Ullén, A; Agerbæk, M

2017-10-28

Vinflunine is to date the only registered agent for second-line treatment of metastatic urothelial cell carcinoma (UCC) in Europe. However, the effect is modest. Pemetrexed has demonstrated some single-agent activity in this disease entity. In order to improve treatment possibilities for UCC patients, a phase I trial (VINTREX) was undertaken to assess the safety of vinflunine and pemetrexed in metastatic UCC patients. A dose escalation design was planned to determine the dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) of a vinflunine/pemetrexed combination. Pemetrexed was added to vinflunine dosed at 280 mg/m2 on day 1 of a 21-day cycle. Three levels of pemetrexed were planned starting at 400 mg/m2. Four patients were enrolled with a mean age of 66 years and with a mean number of prior GC-cycles of 6,8. Two DLT's were observed at the lowest dose-level in cohort 1. One patient experienced grade 4 thrombocytopenia and a second demonstrated hepatobiliary toxicity grade 3 with an increase in alanine aminotransaminase. Most common grade 3 and 4 adverse events were anemia, thrombocytopenia and neutropenia. Three out of four patients received 3 cycles of pemetrexed and vinflunine, all had progressive disease. Based on these observations and due to protocol design, the study was interrupted at dose level 1 for safety reasons. The combined therapy of vinflunine (Javlor®, Pierre Fabre Pharma) and pemetrexed (Alimta®, Eli Lilly) is poorly tolerated in metastatic UCC patients. The combination cannot be recommended for further investigations in metastatic UCC.

FIRST LEGO League Kickoff

NASA Technical Reports Server (NTRS)

2006-01-01

FIRST LEGO League participants listen to Aerospace Education Specialist Chris Copelan explain the playing field for 'Nano Quest' during a recent FLL kickoff event at StenniSphere, the visitor center at NASA Stennis Space Center. The kickoff began the 2006 FLL competition season. Eighty-five teachers, mentors, parents and 9- to 14-year-old students from southern and central Mississippi came to SSC to hear the rules for Nano Quest. The challenge requires teams to spend eight weeks building and programming robots from LEGO Mindstorms kits. They'll battle their creations in local and regional competitions. The Dec. 2 competition at Mississippi Gulf Coast Community College will involve about 200 students. FIRST LEGO League, considered the 'little league' of the FIRST (For Inspiration and Recognition of Science and Technology) Robotics Competition, partners FIRST and the LEGO Group. Competitions aim to inspire and celebrate science and technology using real-world context and hands-on experimentation, and to promote the principles of team play and gracious professionalism. Because NASA advocates robotics and science-technology education, the agency and SSC support FIRST by providing team coaches, mentors and training, as well as competition event judges, referees, audio-visual and other volunteer staff personnel. Two of Mississippi's NASA Explorer Schools, Bay-Waveland Middle and Hattiesburg's Lillie Burney Elementary, were in attendance. The following schools were also represented: Ocean Springs Middle, Pearl Upper Elementary, Long Beach Middle, Jackson Preparatory Academy, North Woolmarket Middle, D'Iberville Middle, West Wortham Middle, Picayune's Roseland Park Baptist Academy and Nicholson Elementary, as well as two home-school groups from McComb and Brandon. Gulfport and Picayune Memorial-Pearl River high schools' FIRST Robotics teams conducted robotics demonstrations for the FLL crowd.

Twenty-first century learning in school systems: the case of the Metropolitan School District of Lawrence Township, Indianapolis, Indiana.

PubMed

Capuano, Marcia; Knoderer, Troy

2006-01-01

To empower students with skills such as information and technological literacy, global awareness and cultural competence, self-direction, and sound reasoning, teachers must master these skills themselves. This chapter examines how the Digital Age Literacy Initiative of the Metropolitan School District of Lawrence Township in Indianapolis, Indiana, which is funded by the Lilly Endowment, incorporated twenty-first century learning through a systemic approach involving teacher training and the use of data. The authors explain the district's content, process, and context goals toward accomplishing its mission of empowering students with the necessary twenty-first century skills to succeed in the digital age. The district places a strong emphasis on professional development for teachers. To support the necessary teacher learning and therefore sustain the work of the initiative, the district has adopted action research, self-assessment, and an online professional development network. To support teachers in implementing new strategies, master teachers serve as digital age literacy coaches. The chapter discusses the initiative's focus on evidence of progress. Through a partnership with the Metiri Group of California, the district has built a range of assessments including online inventories and twenty-first century skill rubrics. For example, the Mankato Survey collected teacher and student data around access, ability, and use of technology in the classroom in 2001 and then in 2004. This research showed significant gains in some technologies across all grade levels and consistent gains in nearly all technologies for middle and high school students. As it moves into the next phase of implementing the Digital Age Literacy Initiative, the district embraces the systemic shifts in school culture necessary to institutionalize twenty-first century learning.

Patterns of long-term and short-term responses in adult patients with attention-deficit/hyperactivity disorder in a completer cohort of 12 weeks or more with atomoxetine.

PubMed

Sobanski, E; Leppämäki, S; Bushe, C; Berggren, L; Casillas, M; Deberdt, W

2015-11-01

Atomoxetine is a well-established pharmacotherapy for adult ADHD. Long-term studies show incremental reductions in symptoms over time. However, clinical experience suggests that patients differ in their response patterns. From 13 Eli Lilly-sponsored studies, we pooled and analyzed data for adults with ADHD who completed atomoxetine treatment at long-term (24 weeks; n=1443) and/or short-term (12 weeks; n=2830) time-points, and had CAARS-Inv:SV total and CGI-S data up to or after these time-points and at Week 0 (i.e. at baseline, when patients first received atomoxetine). The goal was to identify and describe distinct trajectories of response to atomoxetine using hierarchical clustering methods and linear mixed modelling. Based on the homogeneity of changes in CAARS-Inv:SV total scores, 5 response clusters were identified for patients who completed long-term (24 weeks) treatment with atomoxetine, and 4 clusters were identified for patients who completed short-term (12 weeks) treatment. Four of the 5 long-term clusters (comprising 95% of completer patients) showed positive trajectories: 2 faster responding clusters (L1 and L2), and 2 more gradually responding clusters (L3 and L4). Responses (i.e.≥30% reduction in CAARS-Inv:SV total score, and CGI-S score≤3) were observed at 8 and 24 weeks in 80% and 95% of completers in Cluster L1, versus 5% and 48% in Cluster L4. While many adults with ADHD responded relatively rapidly to atomoxetine, others responded more gradually without a clear plateau at 24 weeks. Longer-term treatment may be associated with greater numbers of responders. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

Atomoxetine Increased Effect over Time in Adults with Attention-Deficit/Hyperactivity Disorder Treated for up to 6 Months: Pooled Analysis of Two Double-Blind, Placebo-Controlled, Randomized Trials.

PubMed

Wietecha, Linda A; Clemow, David B; Buchanan, Andrew S; Young, Joel L; Sarkis, Elias H; Findling, Robert L

2016-07-01

Changes in the magnitude of efficacy throughout 26 weeks of atomoxetine treatment, along with impact of dosing, were evaluated in adults with ADHD from two randomized, double-blind, placebo-controlled studies. Pooled placebo (n = 485) and atomoxetine (n = 518) patients, dosed 25, 40, 60, 80 (target dose), or 100 mg daily, were assessed. Change from baseline in Conners' Adult ADHD Rating Scale-Investigator Rated Scale: Screening Version (CAARS) total ADHD symptoms score and Adult ADHD Investigator Symptom Rating Scale (AISRS) total score were analyzed using mixed-model repeated measures, with least squares mean change, effect size, and response rate calculated at 1, 2, 4, 8, 12, 16, 22, and 26 weeks. Decreases on CAARS for atomoxetine- versus placebo-treated patients were consistently statistically significantly greater at every time point beginning at one week (P ≤ 0.006, 0.28 effect size). By 4 weeks, comparison was -13.19 compared with -8.84 (P < 0.0001, 0.45 effect size). By 26 weeks, mean change was -15.42 versus -9.71 (0.52 effect size); increase in effect size over time was most pronounced in the 80 mg group (0.82 effect size). AISRS demonstrated similar results. Atomoxetine response rate (CAARS 50% decrease) continued to increase throughout 26 weeks. Atomoxetine treatment in adults with ADHD was associated with small effect sizes after 4 weeks and moderate effect sizes by 6 months of treatment. The data support increased effect size and response rate over time during longer-term treatment at target dose. © 2016 Eli Lilly and Company. CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.

A Phase 2 Randomized Study of Ramucirumab (IMC-1121B) with or without Dacarbazine in Patients with Metastatic Melanoma

PubMed Central

Carvajal, Richard D.; Wong, Michael K.; Thompson, John A.; Gordon, Michael S.; Lewis, Karl D.; Pavlick, Anna C.; Wolchok, Jedd D.; Rojas, Patrick B.; Schwartz, Jonathan D.; Bedikian, Agop Y.

2017-01-01

SUMMARY Background To evaluate the efficacy and safety of ramucirumab (IMC-1121B; LY3009806), a fully human monoclonal antibody targeting the vascular endothelial growth factor receptor-2, alone and in combination with dacarbazine in chemotherapy-naïve patients with metastatic melanoma (MM). Methods Eligible patients received ramucirumab (10 mg/kg) + dacarbazine (1000 mg/m2) (Arm A) or ramucirumab only (10 mg/kg) (Arm B) every 3 weeks. The primary endpoint was progression-free survival (PFS); secondary endpoints included overall survival (OS), overall response, and safety. Findings Of 106 randomized patients, 102 received study treatment (Arm A, N = 52; Arm B, N = 50). Baseline characteristics were similar in both arms. Median PFS was 2·6 months (Arm A) and 1·7 months (Arm B); median 6-month PFS rates were 30·7% and 17·9% and 12-month PFS rates were 23·7% and 15·6%, respectively. In Arm A, 9 (17·3%) patients had partial response (PR) and 19 (36·5%), stable disease (SD); PR and SD in Arm B were 2 (4·0%) and 21 (42·0%), respectively. Median OS was 8·7 months in Arm A and 11·1 months in Arm B. Patients in both arms tolerated the treatment with limited grade 3/4 toxicities. Interpretation Ramucirumab alone or in combination with dacarbazine was associated with an acceptable safety profile in patients with MM. Although the study was not powered for comparison between treatment arms, PFS appeared greater with combination therapy. Sustained disease control was observed on both study arm Funding Funded by ImClone Systems LLC, a wholly-owned subsidiary of Eli Lilly and Company, Bridgewater, NJ PMID:24930625

Abundance of Plasma Antioxidant Proteins Confers Tolerance to Acute Hypobaric Hypoxia Exposure

PubMed Central

Padhy, Gayatri; Sethy, Niroj Kumar; Ganju, Lilly

2013-01-01

Abstract Padhy, Gayatri, Niroj Kumar Sethy, Lilly Ganju, and Kalpana Bhargava. Abundance of plasma antioxidant proteins confers tolerance to acute hypobaric hypoxia exposure. High Alt Med Biol 14:289–297, 2013—Systematic identification of molecular signatures for hypobaric hypoxia can aid in better understanding of human adaptation to high altitude. In an attempt to identify proteins promoting hypoxia tolerance during acute exposure to high altitude, we screened and identified hypoxia tolerant and susceptible rats based on hyperventilation time to a simulated altitude of 32,000 ft (9754 m). The hypoxia tolerance was further validated by estimating 8-isoprotane levels and protein carbonyls, which revealed that hypoxia tolerant rats possessed significant lower plasma levels as compared to susceptible rats. We used a comparative plasma proteome profiling approach using 2-dimensional gel electrophoresis (2-DGE) combined with MALDI TOF/TOF for both groups, along with an hypoxic control group. This resulted in the identification of 19 differentially expressed proteins. Seven proteins (TTR, GPx-3, PON1, Rab-3D, CLC11, CRP, and Hp) were upregulated in hypoxia tolerant rats, while apolipoprotein A-I (APOA1) was upregulated in hypoxia susceptible rats. We further confirmed the consistent higher expression levels of three antioxidant proteins (PON1, TTR, and GPx-3) in hypoxia-tolerant animals using ELISA and immunoblotting. Collectively, these proteomics-based results highlight the role of antioxidant enzymes in conferring hypoxia tolerance during acute hypobaric hypoxia. The expression of these antioxidant enzymes could be used as putative biomarkers for screening altitude adaptation as well as aiding in better management of altered oxygen pathophysiologies. PMID:24067188

Comparison of standard (self-directed) versus intensive patient training for the human insulin inhalation powder (HIIP) delivery system in patients with type 2 diabetes: efficacy, safety, and training measures.

PubMed

Rosenstock, Julio; Nakano, Masako; Silverman, Bernard L; Sun, Bin; de la Peña, Amparo; Suri, Ajit; Muchmore, Douglas B

2007-02-01

The Lilly/Alkermes human insulin inhalation powder (HIIP) delivery system [AIR (a registered trademark of Alkermes, Inc., Cambridge, MA) Inhaled Insulin System] was designed to be easy to use. Training methods were compared in insulin-naive patients with type 2 diabetes. Patients (n = 102) were randomized to standard or intensive training. With standard training, patients learned how to use the HIIP delivery system by reading directions for use (DFU) and trying on their own. Intensive training included orientation to the HIIP delivery system with individual coaching and inspiratory flow rate training. Both groups received preprandial HIIP + metformin with or without a thiazolidinedione for 4 weeks. Overall 2-h postprandial blood glucose (PPBG) excursion was the primary measure. Noninferiority was defined as the upper limit of the two-sided 95% confidence interval of the mean difference between groups being 1.2 < or = mmol/L. Overall 2-h PPBG excursions (least squares mean +/- SE) at endpoint were -0.11 +/- 0.38 (standard training) and 0.23 +/- 0.36 (intensive training) mmol/L. The mean difference (standard minus intensive training) and two-sided 95% confidence interval were -0.35 (-1.02, 0.33) mmol/L. No statistically or clinically significant differences were observed between training methods in premeal, postmeal, or bedtime blood glucose values, HIIP doses at endpoint, or blood glucose values after a test meal. No discontinuations occurred because of difficulty of use or dislike of the HIIP system. DFU compliance was >90% in both training groups. There were no significant differences between training methods in safety measures. The HIIP delivery system is easy to use, and most patients can learn to use it by reading the DFU without assistance from health care professionals.

Uncertainty in predicting soil hydraulic properties at the hillslope scale with indirect methods

NASA Astrophysics Data System (ADS)

Chirico, G. B.; Medina, H.; Romano, N.

2007-02-01

SummarySeveral hydrological applications require the characterisation of the soil hydraulic properties at large spatial scales. Pedotransfer functions (PTFs) are being developed as simplified methods to estimate soil hydraulic properties as an alternative to direct measurements, which are unfeasible for most practical circumstances. The objective of this study is to quantify the uncertainty in PTFs spatial predictions at the hillslope scale as related to the sampling density, due to: (i) the error in estimated soil physico-chemical properties and (ii) PTF model error. The analysis is carried out on a 2-km-long experimental hillslope in South Italy. The method adopted is based on a stochastic generation of patterns of soil variables using sequential Gaussian simulation, conditioned to the observed sample data. The following PTFs are applied: Vereecken's PTF [Vereecken, H., Diels, J., van Orshoven, J., Feyen, J., Bouma, J., 1992. Functional evaluation of pedotransfer functions for the estimation of soil hydraulic properties. Soil Sci. Soc. Am. J. 56, 1371-1378] and HYPRES PTF [Wösten, J.H.M., Lilly, A., Nemes, A., Le Bas, C., 1999. Development and use of a database of hydraulic properties of European soils. Geoderma 90, 169-185]. The two PTFs estimate reliably the soil water retention characteristic even for a relatively coarse sampling resolution, with prediction uncertainties comparable to the uncertainties in direct laboratory or field measurements. The uncertainty of soil water retention prediction due to the model error is as much as or more significant than the uncertainty associated with the estimated input, even for a relatively coarse sampling resolution. Prediction uncertainties are much more important when PTF are applied to estimate the saturated hydraulic conductivity. In this case model error dominates the overall prediction uncertainties, making negligible the effect of the input error.

FIRST LEGO League Kickoff

NASA Image and Video Library

2006-09-23

FIRST LEGO League participants listen to Aerospace Education Specialist Chris Copelan explain the playing field for 'Nano Quest' during a recent FLL kickoff event at StenniSphere, the visitor center at NASA Stennis Space Center. The kickoff began the 2006 FLL competition season. Eighty-five teachers, mentors, parents and 9- to 14-year-old students from southern and central Mississippi came to SSC to hear the rules for Nano Quest. The challenge requires teams to spend eight weeks building and programming robots from LEGO Mindstorms kits. They'll battle their creations in local and regional competitions. The Dec. 2 competition at Mississippi Gulf Coast Community College will involve about 200 students. FIRST LEGO League, considered the 'little league' of the FIRST (For Inspiration and Recognition of Science and Technology) Robotics Competition, partners FIRST and the LEGO Group. Competitions aim to inspire and celebrate science and technology using real-world context and hands-on experimentation, and to promote the principles of team play and gracious professionalism. Because NASA advocates robotics and science-technology education, the agency and SSC support FIRST by providing team coaches, mentors and training, as well as competition event judges, referees, audio-visual and other volunteer staff personnel. Two of Mississippi's NASA Explorer Schools, Bay-Waveland Middle and Hattiesburg's Lillie Burney Elementary, were in attendance. The following schools were also represented: Ocean Springs Middle, Pearl Upper Elementary, Long Beach Middle, Jackson Preparatory Academy, North Woolmarket Middle, D'Iberville Middle, West Wortham Middle, Picayune's Roseland Park Baptist Academy and Nicholson Elementary, as well as two home-school groups from McComb and Brandon. Gulfport and Picayune Memorial-Pearl River high schools' FIRST Robotics teams conducted robotics demonstrations for the FLL crowd.

The tau positron-emission tomography tracer AV-1451 binds with similar affinities to tau fibrils and monoamine oxidases.

PubMed

Vermeiren, Céline; Motte, Philippe; Viot, Delphine; Mairet-Coello, Georges; Courade, Jean-Philippe; Citron, Martin; Mercier, Joël; Hannestad, Jonas; Gillard, Michel

2018-02-01

Lilly/Avid's AV-1451 is one of the most advanced tau PET tracers in the clinic. Although results obtained in Alzheimer's disease patients are compelling, discrimination of tracer uptake in healthy individuals and patients with supranuclear palsy (PSP) is less clear as there is substantial overlap of signal in multiple brain regions. Moreover, accurate quantification of [ 18 F]AV-1451 uptake in Alzheimer's disease may not be possible. The aim of the present study was to characterize the in vitro binding of AV-1451 to understand and identify potential off-target binding that could explain the poor discrimination observed in PSP patients. [ 3 H]AV-1451 and AV-1451 were characterized in in vitro binding assays using recombinant and native proteins/tissues from postmortem samples of controls and Alzheimer's disease and PSP patients. [ 3 H]AV-1451 binds to multiple sites with nanomolar affinities in brain homogenates and to tau fibrils isolated from Alzheimer's disease or PSP patients. [ 3 H]AV-1451 also binds with similarly high affinities in brain homogenates devoid of tau pathology. This unexpected binding was demonstrated to be because of nanomolar affinities of [ 3 H]AV-1451 for monoamine oxidase A and B enzymes. High affinity of AV-1451 for monoamine oxidase proteins may limit its utility as a tau PET tracer in PSP and Alzheimer's disease because of high levels of monoamine oxidase expression in brain regions also affected by tau deposition, especially if monoamine oxidase levels change over time or with a treatment intervention. © 2017 International Parkinson and Movement Disorder Society. © 2017 International Parkinson and Movement Disorder Society.

Assessment of mitochondrial membrane potential in HEI-OC1 and LLC-PK1 cells treated with gentamicin and mitoquinone.

PubMed

Ng, Maria Raye Anne V; Antonelli, Patrick J; Joseph, Jerin; Dirain, Carolyn Ojano

2015-04-01

To determine the effects of concurrent treatment with gentamicin and the mitochondria-targeted antioxidant mitoquinone (MitoQ; which may prevent gentamicin ototoxicity) on change in the mitochondrial membrane potential (Δψ(m)), a precursor of apoptosis. Prospective and controlled. Academic research laboratory. LLC-PK1 (Lilly Laboratories Culture-Pig Kidney Type 1) and HEI-OC1 (House Ear Institute Organ of Corti 1) cells-renal and auditory cell lines, respectively-were used in this study. Δψ(m) was assessed by flow cytometry through the MitoProbe JC-1 Kit for Flow Cytometry in untreated LLC-PK1 and HEI-OC1 cells and cells exposed to low- (100µM) or high- (2000µM) dose gentamicin for 24 hours, with and without 0.5µM each of MitoQ or idebenone (IDB; an untargeted ubiquinone). Δψ(m) was not different in untreated LLC-PK1 cells and cells coincubated with low-dose gentamicin and MitoQ or IDB (P > .05). In HEI-OC1 cells, coincubation with low-dose gentamicin and MitoQ decreased Δψ(m) (P = .002). Coincubation of LLC-PK1 cells with high-dose gentamicin and DMSO, MitoQ, or IDB depolarized Δψ(m) (P < .0001), with MitoQ depolarizing the Δψ(m) to a greater extent than that of IDB (P = .03). In contrast, HEI-OC1 cells demonstrated a hyperpolarized Δψ(m) when coincubated with high-dose gentamicin and DMSO, MitoQ, or IDB (P < .001). The combination of gentamicin and MitoQ holds the potential to disrupt Δψ(m). This suggests a heightened need to monitor for toxicity in patients receiving both agents. © American Academy of Otolaryngology—Head and Neck Surgery Foundation 2014.

Seasonal affective disorder and non-seasonal affective disorders: results from the NESDA study

PubMed Central

Roest, Annelieke M.; Bos, Elisabeth H.; Meesters, Ybe; Penninx, Brenda W.J.H.; Nolen, Willem A.; de Jonge, Peter

2017-01-01

Background Seasonal affective disorder (SAD) is considered to be a subtype of depression. Aims To compare the clinical picture of SAD to non-seasonal affective disorders (non-SADs). Method Diagnoses according to the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) were established in 2185 participants of the Netherlands Study of Depression and Anxiety. The Seasonal Pattern Assessment Questionnaire was administered to diagnose SAD. Symptoms of depression and anxiety were measured with the Inventory of Depressive Symptoms, the Beck Anxiety Inventory and the Fear Questionnaire. Results Participants with SAD, participants with a lifetime bipolar disorder and participants with a lifetime comorbid anxiety and depressive disorder scored highest in terms of psychopathology in the past year. The seasonal distribution of major depressive episodes was not different for participants with or without SAD. Conclusions SAD may be a measure of severity of depression with a subjectively perceived worsening of symptoms in the winter months. Declaration of interest Y.M. has received research funding and served as a consultant for Royal Philips Electronics NV and The Litebook Company Ltd. W.A.N. has received grants from the Netherlands Organization for Health Research and Development, the European Union, the Stanley Medical Research Institute, Astra Zeneca, Eli Lilly, GlaxoSmithKline and Wyeth; has received honoraria/speaker’s fees from Astra Zeneca, Pfizer, Servier and Wyeth; and has served in advisory boards for Astra Zeneca, Pfizer and Servier. Copyright and usage © The Royal College of Psychiatrists 2017. This is an open access article distributed under the terms of the Creative Commons Non-Commercial, No Derivatives (CC BY-NC-ND) license. PMID:28904813

Prasugrel versus clopidogrel for acute coronary syndromes without revascularization.

PubMed

Roe, Matthew T; Armstrong, Paul W; Fox, Keith A A; White, Harvey D; Prabhakaran, Dorairaj; Goodman, Shaun G; Cornel, Jan H; Bhatt, Deepak L; Clemmensen, Peter; Martinez, Felipe; Ardissino, Diego; Nicolau, Jose C; Boden, William E; Gurbel, Paul A; Ruzyllo, Witold; Dalby, Anthony J; McGuire, Darren K; Leiva-Pons, Jose L; Parkhomenko, Alexander; Gottlieb, Shmuel; Topacio, Gracita O; Hamm, Christian; Pavlides, Gregory; Goudev, Assen R; Oto, Ali; Tseng, Chuen-Den; Merkely, Bela; Gasparovic, Vladimir; Corbalan, Ramon; Cinteză, Mircea; McLendon, R Craig; Winters, Kenneth J; Brown, Eileen B; Lokhnygina, Yuliya; Aylward, Philip E; Huber, Kurt; Hochman, Judith S; Ohman, E Magnus

2012-10-04

The effect of intensified platelet inhibition for patients with unstable angina or myocardial infarction without ST-segment elevation who do not undergo revascularization has not been delineated. In this double-blind, randomized trial, in a primary analysis involving 7243 patients under the age of 75 years receiving aspirin, we evaluated up to 30 months of treatment with prasugrel (10 mg daily) versus clopidogrel (75 mg daily). In a secondary analysis involving 2083 patients 75 years of age or older, we evaluated 5 mg of prasugrel versus 75 mg of clopidogrel. At a median follow-up of 17 months, the primary end point of death from cardiovascular causes, myocardial infarction, or stroke among patients under the age of 75 years occurred in 13.9% of the prasugrel group and 16.0% of the clopidogrel group (hazard ratio in the prasugrel group, 0.91; 95% confidence interval [CI], 0.79 to 1.05; P=0.21). Similar results were observed in the overall population. The prespecified analysis of multiple recurrent ischemic events (all components of the primary end point) suggested a lower risk for prasugrel among patients under the age of 75 years (hazard ratio, 0.85; 95% CI, 0.72 to 1.00; P=0.04). Rates of severe and intracranial bleeding were similar in the two groups in all age groups. There was no significant between-group difference in the frequency of nonhemorrhagic serious adverse events, except for a higher frequency of heart failure in the clopidogrel group. Among patients with unstable angina or myocardial infarction without ST-segment elevation, prasugrel did not significantly reduce the frequency of the primary end point, as compared with clopidogrel, and similar risks of bleeding were observed. (Funded by Eli Lilly and Daiichi Sankyo; TRILOGY ACS ClinicalTrials.gov number, NCT00699998.).

The Citizen Cyberscience Lectures - 1) Mobile phones and Africa: a success story 2) Citizen Problem Solving

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

Ibrahim, Mo

2009-10-28

Mobile phones and Africa: a success story Dr. Mo Ibrahim, Mo Ibrahim Foundation Citizen Problem Solving Dr. Alpheus Bingham, InnoCentive The Citizen Cyberscience Lectures are hosted by the partners of the Citizen Cyberscience Centre, CERN, The UN Institute of Training and Research and the University of Geneva. The goal of the Lectures is to provide an inspirational forum for participants from the various international organizations and academic institutions in Geneva to explore how information technology is enabling greater citizen participation in tackling global development challenges as well as global scientific research. The first Citizen Cyberscience Lectures will welcome two speakersmore » who have both made major innovative contributions in this area. Dr. Mo Ibrahim, founder of Celtel International, one of Africa’s most successful mobile network operators, will talk about “Mobile phones and Africa: a success story”. Dr. Alpheus Bingham, founder of InnoCentive, a Web-based community that solves industrial R&D; challenges, will discuss “Citizen Problem Solving”. The Citizen Cyberscience Lectures are open and free of charge. Participants from outside CERN must register by sending an email to Yasemin.Hauser@cern.ch BEFORE the 23rd october to be able to access CERN. THE LECTURES Mobile phones and Africa: a success story Dr. Mo Ibrahim, Mo Ibrahim Foundation Abstract The introduction of mobile phones into Africa changed the continent, enabling business and the commercial sector, creating directly and indirectly, millions of jobs. It enriched the social lives of many people. Surprisingly, it supported the emerging civil society and advanced the course of democracy Bio Dr Mo Ibrahim is a global expert in mobile communications with a distinguished academic and business career. In 1998, Dr Ibrahim founded Celtel International to build and operate mobile networks in Africa. Celtel became one of Africa’s most successful companies with operations in 15 countries, covering more than a third of the continent’s population and investing more than US 750 millionin Africa.The company was sold to MTC Kuwaitin 2005 for 3.4billion. In 2006 Dr Ibrahim established the Mo Ibrahim Foundation to support great African leadership. The Foundation focuses on two major initiatives to stimulate debate around, and improve the quality of, governance in Africa. The Ibrahim Prize for Achievement in African Leadership recognises and celebrates excellence; and the Ibrahim Index of African Governance provides civil society with a comprehensive and quantifiable tool to promote government accountability. Dr Ibrahim is also Founding Chairman of Satya Capital Ltd, an investment company focused on opportunities in Africa. Dr Ibrahim has been awarded an Honorary Doctorate by the University of London’s School of Oriental and African Studies, the University of Birmingham and De Montfort University, Leicester as well as an Honorary Fellowship Award from the London Business School. He has also received the Chairman’s Award for Lifetime Achievement from the GSM Association in 2007 and the Economists Innovation Award 2007 for Social & Economic Innovation. In 2008 Dr Ibrahim was presented with the BNP Paribas Prize for Philanthropy, and also listed by TIME magazine as one of the 100 most influential people in the world. Citizen Problem Solving Dr. Alpheus Bingham, InnoCentive Abstract American playwright Damien Runyon (Guys and Dolls) once remarked, "the race is not always to the swift, nor the victory to the strong -- but that IS how you bet." Not only does a system of race handicapping follow from this logic, but the whole notion of expertise and technical qualifications. Such 'credentials' allow one to 'bet' on who might most likely solve a difficult challenge, whether as consultant, contractor or employee. Of course, the approach would differ if one were allowed to bet AFTER the race. When such systems came into broad use, i.e., chat rooms, usenets, innocentive, etc., and were subsequently studied, it was often found that the greatest probability of solution lies in the "long tail" of the function rather than in the head representing formally vetted 'experts.' Insight into a problem is often the intersection of training, experience, metaphor and provocation (think Archimedes). Examples of "citizens" outside a targeted field of expertise providing uniques solutions will illustrate the principles involved. Bio Dr. Alph Bingham is a pioneer in the field of open innovation and an advocate of collaborative approaches to research and development. He is co-founder, and former president and chief executive officer of InnoCentive Inc., a Web-based community that matches companies facing R&D; challenges with scientists who propose solutions. Through InnoCentive, a platform that leverages the ability to connect to a whole planet of people through the Internet, organizations can access individuals – problem solvers – who might never have been found. Alph spent more than 25 years with Eli Lilly and Company, and offers deep experience in pharmaceutical research and development, research acquisitions and collaborations, and R&D; strategic planning. During his career he was instrumental in creating and developing Eli Lilly's portfolio management process as well as establishing the divisions of Research Acquisitions, the Office of Alliance Management and e.Lilly, a business innovation unit, from which various other ventures were spun out that create the advantages of open and networked organizational structures, including: InnoCentive, YourEncore, Inc., Coalesix, Inc., Maaguzi, Inc., Indigo Biosystems, Seriosity, Chorus and Collaborative Drug Discovery, Inc. He currently serves on the Board of Directors of InnoCentive, Inc., and Collaborative Drug Discovery, Inc.; the advisory boards of the Center for Collective Intelligence (MIT), and the Business Innovation Factory, as well as a member of the board of trustees of the Bankinter Foundation for Innovation in Madrid. He has lectured extensively at both national and international events and serves as a Visiting Scholar at the National Center for Supercomputing Application at the University of Illinois at Champaign-Urbana. He is also the former chairman of the Board of Editors of the Research Technology Management Journal. Dr. Bingham was the recipient of the Economist's Fourth Annual Innovation Summit "Business Process Award" for InnoCentive. He was also named as one of Project Management Institute's "Power 50" leaders in October 2005. Dr. Bingham received a Ph.D. in organic chemistry from Stanford University.« less

Patterns of Adherence to Oral Atypical Antipsychotics Among Patients Diagnosed with Schizophrenia.

PubMed

MacEwan, Joanna P; Forma, Felicia M; Shafrin, Jason; Hatch, Ainslie; Lakdawalla, Darius N; Lindenmayer, Jean-Pierre

2016-11-01

Poor medication adherence contributes to negative treatment response, symptom relapse, and hospitalizations in schizophrenia. Many health plans use claims-based measures like medication possession ratios or proportion of days covered (PDC) to measure patient adherence to antipsychotics. Classifying patients solely on the basis of a single average PDC measure, however, may mask clinically meaningful variations over time in how patients arrive at an average PDC level. To model patterns of medication adherence evolving over time for patients with schizophrenia who initiated treatment with an oral atypical antipsychotic and, based on these patterns, to identify groups of patients with different adherence behaviors. We analyzed health insurance claims for patients aged ≥ 18 years with schizophrenia and newly prescribed oral atypical antipsychotics in 2007-2013 from 3 U.S. insurance claims databases: Truven MarketScan (Medicaid and commercial) and Humana (Medicare). Group-based trajectory modeling (GBTM) was used to stratify patients into groups with distinct trends in adherence and to estimate trends for each group. The response variable was the probability of adherence (defined as PDC ≥ 80%) in each 30-day period after the patient initiated antipsychotic therapy. GBTM proceeds from the premise that there are multiple distinct adherence groups. Patient demographics, health status characteristics, and health care resource use metrics were used to identify differences in patient populations across adherence trajectory groups. Among the 29,607 patients who met the inclusion criteria, 6 distinct adherence trajectory groups emerged from the data: adherent (33%); gradual discontinuation after 3 months (15%), 6 months (7%), and 9 months (5%); stop-start after 6 months (15%); and immediate discontinuation (25%). Compared to patients 18-24 years of age in the adherent group, patients displaying a stop-start pattern after 6 months had greater odds of having a history of drug abuse (OR = 1.46; 95% CI = 1.26-1.66; P < 0.001), alcohol abuse (OR = 1.34; 95% CI = 1.14-1.53; P< 0.001), and a codiagnosis of major depressive disorder (OR = 1.24; 95% CI = 1.05-1.44; P < 0.001) and were less likely to be aged 35-54 years (OR = 0.66; 95% CI = 0.46-0.85; P < 0.001). Longitudinal medication adherence patterns can be expressed as distinct trajectories associated with specific patient characteristics and health care utilization patterns. We found 6 distinct patterns of adherence to antipsychotics over 12 months. Patients in different groups may warrant different types of clinical interventions to prevent hospitalizations, longer hospital stays, and increased clinical complexity. For example, clinicians may consider regular home visits, assertive community treatment, and other related interventions for patients at high risk of immediate discontinuation. Health plans should consider supplementing claims-based adherence measures with new technologies that are able to track patient adherence patterns over time. Otsuka Pharmaceutical Development & Commercialization provided support for this research. MacEwan and Shafrin are employees of Precision Health Economics, which was contracted by Otsuka Pharmaceutical Development & Commercialization to conduct this study. Lakdawalla is the Chief Scientific Officer and a founding partner of Precision Health Economics. Forma is an employee of Otsuka Pharmaceutical Development & Commercialization. Hatch is a former employee of Otsuka Pharmaceutical Development & Commercialization and is a current employee of ODH, Inc. Lindenmayer has received grant/research support from Janssen, Lilly, AstraZeneca, Johnson & Johnson, Pfizer, BMS, Otsuka, Dainippon, and Roche and is a consultant for Janssen, Lilly, Merck, Shire, and Lundbeck. Portions of this study were presented as a poster at the American Society of Clinical Psychopharmacology Annual Meeting in Miami Beach, Florida; June 23, 2015; and at the 28th Annual U.S. Psychiatric and Mental Health Congress; San Diego, California; September 12, 2015. Study concept and design were contributed by Forma, Ladkawalla, MacEwan, and Shafrin, along with Hatch and Lindenmayer. MacEwan, Shafrin, Forma, and Lakdawalla collected the data, along with Hatch and Lindenmayer. Data interpretation was performed by Hatch, Lindenmayer, MacEwan, and Shafrin, assisted by Forma and Lakdawalla. The manuscript was written and revised by MacEwan, Forma, and Shafrin, along with Hatch Lakdawalla, and Lindenmayer.

The Citizen Cyberscience Lectures - 1) Mobile phones and Africa: a success story 2) Citizen Problem Solving

ScienceCinema

Ibrahim, Mo

2018-05-25

Mobile phones and Africa: a success story Dr. Mo Ibrahim, Mo Ibrahim Foundation Citizen Problem Solving Dr. Alpheus Bingham, InnoCentive The Citizen Cyberscience Lectures are hosted by the partners of the Citizen Cyberscience Centre, CERN, The UN Institute of Training and Research and the University of Geneva. The goal of the Lectures is to provide an inspirational forum for participants from the various international organizations and academic institutions in Geneva to explore how information technology is enabling greater citizen participation in tackling global development challenges as well as global scientific research. The first Citizen Cyberscience Lectures will welcome two speakers who have both made major innovative contributions in this area. Dr. Mo Ibrahim, founder of Celtel International, one of Africa’s most successful mobile network operators, will talk about “Mobile phones and Africa: a success story”. Dr. Alpheus Bingham, founder of InnoCentive, a Web-based community that solves industrial R&D; challenges, will discuss “Citizen Problem Solving”. The Citizen Cyberscience Lectures are open and free of charge. Participants from outside CERN must register by sending an email to Yasemin.Hauser@cern.ch BEFORE the 23rd october to be able to access CERN. THE LECTURES Mobile phones and Africa: a success story Dr. Mo Ibrahim, Mo Ibrahim Foundation Abstract The introduction of mobile phones into Africa changed the continent, enabling business and the commercial sector, creating directly and indirectly, millions of jobs. It enriched the social lives of many people. Surprisingly, it supported the emerging civil society and advanced the course of democracy Bio Dr Mo Ibrahim is a global expert in mobile communications with a distinguished academic and business career. In 1998, Dr Ibrahim founded Celtel International to build and operate mobile networks in Africa. Celtel became one of Africa’s most successful companies with operations in 15 countries, covering more than a third of the continent’s population and investing more than US 750 millionin Africa.The company was sold to MTC Kuwaitin 2005 for 3.4billion. In 2006 Dr Ibrahim established the Mo Ibrahim Foundation to support great African leadership. The Foundation focuses on two major initiatives to stimulate debate around, and improve the quality of, governance in Africa. The Ibrahim Prize for Achievement in African Leadership recognises and celebrates excellence; and the Ibrahim Index of African Governance provides civil society with a comprehensive and quantifiable tool to promote government accountability. Dr Ibrahim is also Founding Chairman of Satya Capital Ltd, an investment company focused on opportunities in Africa. Dr Ibrahim has been awarded an Honorary Doctorate by the University of London’s School of Oriental and African Studies, the University of Birmingham and De Montfort University, Leicester as well as an Honorary Fellowship Award from the London Business School. He has also received the Chairman’s Award for Lifetime Achievement from the GSM Association in 2007 and the Economists Innovation Award 2007 for Social & Economic Innovation. In 2008 Dr Ibrahim was presented with the BNP Paribas Prize for Philanthropy, and also listed by TIME magazine as one of the 100 most influential people in the world. Citizen Problem Solving Dr. Alpheus Bingham, InnoCentive Abstract American playwright Damien Runyon (Guys and Dolls) once remarked, "the race is not always to the swift, nor the victory to the strong -- but that IS how you bet." Not only does a system of race handicapping follow from this logic, but the whole notion of expertise and technical qualifications. Such 'credentials' allow one to 'bet' on who might most likely solve a difficult challenge, whether as consultant, contractor or employee. Of course, the approach would differ if one were allowed to bet AFTER the race. When such systems came into broad use, i.e., chat rooms, usenets, innocentive, etc., and were subsequently studied, it was often found that the greatest probability of solution lies in the "long tail" of the function rather than in the head representing formally vetted 'experts.' Insight into a problem is often the intersection of training, experience, metaphor and provocation (think Archimedes). Examples of "citizens" outside a targeted field of expertise providing uniques solutions will illustrate the principles involved. Bio Dr. Alph Bingham is a pioneer in the field of open innovation and an advocate of collaborative approaches to research and development. He is co-founder, and former president and chief executive officer of InnoCentive Inc., a Web-based community that matches companies facing R&D; challenges with scientists who propose solutions. Through InnoCentive, a platform that leverages the ability to connect to a whole planet of people through the Internet, organizations can access individuals – problem solvers – who might never have been found. Alph spent more than 25 years with Eli Lilly and Company, and offers deep experience in pharmaceutical research and development, research acquisitions and collaborations, and R&D; strategic planning. During his career he was instrumental in creating and developing Eli Lilly's portfolio management process as well as establishing the divisions of Research Acquisitions, the Office of Alliance Management and e.Lilly, a business innovation unit, from which various other ventures were spun out that create the advantages of open and networked organizational structures, including: InnoCentive, YourEncore, Inc., Coalesix, Inc., Maaguzi, Inc., Indigo Biosystems, Seriosity, Chorus and Collaborative Drug Discovery, Inc. He currently serves on the Board of Directors of InnoCentive, Inc., and Collaborative Drug Discovery, Inc.; the advisory boards of the Center for Collective Intelligence (MIT), and the Business Innovation Factory, as well as a member of the board of trustees of the Bankinter Foundation for Innovation in Madrid. He has lectured extensively at both national and international events and serves as a Visiting Scholar at the National Center for Supercomputing Application at the University of Illinois at Champaign-Urbana. He is also the former chairman of the Board of Editors of the Research Technology Management Journal. Dr. Bingham was the recipient of the Economist's Fourth Annual Innovation Summit "Business Process Award" for InnoCentive. He was also named as one of Project Management Institute's "Power 50" leaders in October 2005. Dr. Bingham received a Ph.D. in organic chemistry from Stanford University.

AIR insulin capsules of different dose strengths may be combined to yield equivalent pharmacokinetics and glucodynamics.

PubMed

de la Peña, Amparo; Seger, Mary; Rave, Klaus; Heinemann, Lutz; Silverman, Bernard; Muchmore, Douglas B

2009-09-01

In order to assess pharmacokinetic (PK) and glucodynamic (GD) attributes relevant to the end user of an inhaled insulin, this study examined the exposure and GD effect of doses of AIR inhaled insulin (Eli Lilly and Co., Indianapolis, IN) (AIR is a registered trademark of Alkermes, Inc., Cambridge, MA) by combining capsules of different strengths in healthy subjects. Fifty-nine healthy, nonsmoking, male or female subjects with normal pulmonary function were enrolled in an open-label, randomized, crossover study. Subjects underwent up to five euglycemic glucose clamp procedures, separated by 5-18 days. The five AIR insulin treatments tested included one 6 unit-equivalent (U-eq) capsule containing 2.6 mg of insulin, three 2 U-eq (0.9 mg) capsules (2.7 mg total), one 10 U-eq (3.9 mg) capsule, one 6 U-eq capsule plus two 2 U-eq capsules (4.4 mg total), and two 10 U-eq capsules (7.8 mg total). Samples for PK and GD assessments were taken up to 10 h post-dose. Based on both PK (area under the curve from time 0 to time of return to baseline and maximum concentration) and GD (total amount of glucose infused and maximum glucose infusion rate) responses, administration of a 6 U-eq capsule was equivalent to three 2 U-eq capsules; 90% confidence intervals for the ratios were contained within the interval (0.8, 1.25). Similarly, both overall exposure and glucodynamic response after administration of a 10 U-eq capsule were comparable to the 6 U-eq plus two 2 U-eq capsule combination. AIR insulin exhibited PK dose proportionality and dose-dependent increases in GD responses over the 2.6-7.8 mg dose range. AIR insulin exhibited dose strength interchangeability and dose proportionality after single-dose administration in healthy subjects.

A comparison between simplified and intensive dose-titration algorithms using AIR inhaled insulin for insulin-naive patients with type 2 diabetes in a randomized noninferiority trial.

PubMed

Mathieu, C; Cuddihy, R; Arakaki, R F; Belin, R M; Planquois, J-M; Lyons, J N; Heilmann, C R

2009-09-01

Insulin initiation and optimization is a challenge for patients with type 2 diabetes. Our objective was to determine whether safety and efficacy of AIR inhaled insulin (Eli Lilly and Co., Indianapolis, IN) (AIR is a registered trademark of Alkermes, Inc., Cambridge, MA) using a simplified regimen was noninferior to an intensive regimen. This was an open-label, randomized study in insulin-naive adults not optimally controlled by oral antihyperglycemic medications. Simplified titration included a 6 U per meal AIR insulin starting dose. Individual doses were adjusted at mealtime in 2-U increments from the previous day's four-point self-monitored blood glucose (SMBG) (total < or =6 U). Starting Air insulin doses for intensive titration were based on fasting blood glucose, gender, height, and weight. Patients conducted four-point SMBG daily for the study duration. Insulin doses were titrated based on the previous 3 days' mean SMBG (total < or =8 U). End point hemoglobin A1C (A1C) was 7.07 +/- 0.09% and 6.87 +/- 0.09% for simplified (n = 178) and intensive (n = 180) algorithms, respectively. Noninferiority between algorithms was not established. The fasting blood glucose (least squares mean +/- standard error) values for the simplified (137.27 +/- 3.42 mg/dL) and intensive (133.13 +/- 3.42 mg/dL) algorithms were comparable. Safety profiles were comparable. The hypoglycemic rate at 4, 8, 12, and 24 weeks was higher in patients receiving intensive titration (all P < .0001). The nocturnal hypoglycemic rate for patients receiving intensive titration was higher than for those receiving simplified titration at 8 (P < 0.015) and 12 weeks (P < 0.001). Noninferiority between the algorithms, as measured by A1C, was not demonstrated. This finding re-emphasizes the difficulty of identifying optimal, simplified insulin regimens for patients.

Impact of pretreatment with antidepressants on the efficacy of duloxetine in terms of mood symptoms and functioning: an analysis of 15 pooled major depressive disorder studies.

PubMed

Barros, Bruno R; Schacht, Alexander; Happich, Michael; Televantou, Foula; Berggren, Lovisa; Walker, Daniel J; Dueñas, Hector J

2014-01-01

This post hoc analysis aimed to determine whether patients with major depressive disorder (MDD) in duloxetine trials who were antidepressant naive or who were previously exposed to antidepressants exhibited differences in efficacy and functioning. Data were pooled from 15 double-blind, placebo- and/or active-controlled duloxetine trials of adult patients with MDD conducted by Eli Lilly and Company. The individual studies took place between March 2000 and November 2009. Data were analyzed using 4 pretreatment subgroups: first-episode never treated, multiple-episode never treated, treated previously only with selective serotonin reuptake inhibitors (SSRIs), and previously treated with antidepressants other than just SSRIs. Measures included the 17-item Hamilton Depression Rating Scale (HDRS-17) total and somatic symptom subscale scores, Montgomery-Asberg Depression Rating Scale (MADRS) total score, and Sheehan Disability Scale total score. Response rates (50% and 30%) were based on the HDRS-17 total score and remission rates on either the HDRS-17 or MADRS total score. Response and remission rates were significantly greater (P < .05 in 11 of 12 comparisons) for duloxetine versus placebo in the 4 subgroups. A trend of greater response and remission occurred for first-episode versus multiple-episode patients; both groups were generally higher than the antidepressant-treated groups. Mean changes in efficacy measures were mostly significantly greater (P < .05 in 13 of 16 comparisons) for duloxetine versus placebo within each pretreatment subgroup, with some (P < .05 in 2 of 24 comparisons) significant interaction effects between subgroups on HDRS-17 total and somatic symptoms scores. Duloxetine was generally superior to placebo on response and remission rates and in mean change on efficacy measures. Response and remission rates were numerically greater for first-episode versus multiple-episode and drug-treated patients. Mean change differences on efficacy measures among the 4 subgroups were inconsistent. Duloxetine showed a similar therapeutic effect independent of episode frequency and antidepressant pretreatment.

pH measurement and a rational and practical pH control strategy for high throughput cell culture system.

PubMed

Zhou, Haiying; Purdie, Jennifer; Wang, Tongtong; Ouyang, Anli

2010-01-01

The number of therapeutic proteins produced by cell culture in the pharmaceutical industry continues to increase. During the early stages of manufacturing process development, hundreds of clones and various cell culture conditions are evaluated to develop a robust process to identify and select cell lines with high productivity. It is highly desirable to establish a high throughput system to accelerate process development and reduce cost. Multiwell plates and shake flasks are widely used in the industry as the scale down model for large-scale bioreactors. However, one of the limitations of these two systems is the inability to measure and control pH in a high throughput manner. As pH is an important process parameter for cell culture, this could limit the applications of these scale down model vessels. An economical, rapid, and robust pH measurement method was developed at Eli Lilly and Company by employing SNARF-4F 5-(-and 6)-carboxylic acid. The method demonstrated the ability to measure the pH values of cell culture samples in a high throughput manner. Based upon the chemical equilibrium of CO(2), HCO(3)(-), and the buffer system, i.e., HEPES, we established a mathematical model to regulate pH in multiwell plates and shake flasks. The model calculates the required %CO(2) from the incubator and the amount of sodium bicarbonate to be added to adjust pH to a preset value. The model was validated by experimental data, and pH was accurately regulated by this method. The feasibility of studying the pH effect on cell culture in 96-well plates and shake flasks was also demonstrated in this study. This work shed light on mini-bioreactor scale down model construction and paved the way for cell culture process development to improve productivity or product quality using high throughput systems. Copyright 2009 American Institute of Chemical Engineers

Topical oxygen wound therapies for chronic wounds: a review.

PubMed

Dissemond, J; Kröger, K; Storck, M; Risse, A; Engels, P

2015-02-01

Chronic wounds are an increasing problem in our ageing population and can arise in many different ways. Over the past decades it has become evident that sufficient oxygen supply is an essential factor of appropriate wound healing. Sustained oxygen deficit has a detrimental impact on wound healing, especially for patients with chronic wounds. This has been proven for wounds associated with peripheral arterial occlusive disease (PAOD) and diabetic foot ulcers (particularly in combination with PAOD). However, this is still under debate for other primary diseases. In the past few years several different new therapeutic approaches for topical oxygen therapies have been developed to support wound healing. These tend to fall into one of four categories: (1) delivery of pure oxygen either under pressurised or (2) ambient condition, (3) chemical release of oxygen via an enzymatic reaction or (4) increase of oxygen by facilitated diffusion using oxygen binding and releasing molecules. In this review article, the available therapeutic topical oxygen-delivering approaches and their impact on wound healing are presented and critically discussed. A summary of clinical data, daily treatment recommendations and practicability is provided. J. Dissemond received an honorarium for lectures, advisory boards and/or clinical studies from the following companies: 3M, B. Braun, BSN, Coloplast, Convatec, Draco, Hartmann, KCI, Lohmann&Rauscher, Medoderm, Merz, Sastomed, Systagenix, UCB-Pharma, Urgo. K. Kröger received an honorarium for lectures, advisory boards and/or clinical studies from the following companies: Bayer, Sanofi, GSK, Hartmann, Sastomed, UCB-Pharma, Urgo. M. Storck received an honorarium for lectures for the following companies: KCI, Systagenix, and UCB-Pharma. A. Risse received an honorarium for lectures, advisory boards and/or clinical studies from the following companies: Bracco, Coloplast, Draco, Lilly Deutschland, NovoNordisk, Sastomed, Urgo. P. Engels received an honorarium for lectures, and consulting from the following companies: Sastomed, Oculus.

Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes.

PubMed

Zinman, Bernard; Wanner, Christoph; Lachin, John M; Fitchett, David; Bluhmki, Erich; Hantel, Stefan; Mattheus, Michaela; Devins, Theresa; Johansen, Odd Erik; Woerle, Hans J; Broedl, Uli C; Inzucchi, Silvio E

2015-11-26

The effects of empagliflozin, an inhibitor of sodium-glucose cotransporter 2, in addition to standard care, on cardiovascular morbidity and mortality in patients with type 2 diabetes at high cardiovascular risk are not known. We randomly assigned patients to receive 10 mg or 25 mg of empagliflozin or placebo once daily. The primary composite outcome was death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke, as analyzed in the pooled empagliflozin group versus the placebo group. The key secondary composite outcome was the primary outcome plus hospitalization for unstable angina. A total of 7020 patients were treated (median observation time, 3.1 years). The primary outcome occurred in 490 of 4687 patients (10.5%) in the pooled empagliflozin group and in 282 of 2333 patients (12.1%) in the placebo group (hazard ratio in the empagliflozin group, 0.86; 95.02% confidence interval, 0.74 to 0.99; P=0.04 for superiority). There were no significant between-group differences in the rates of myocardial infarction or stroke, but in the empagliflozin group there were significantly lower rates of death from cardiovascular causes (3.7%, vs. 5.9% in the placebo group; 38% relative risk reduction), hospitalization for heart failure (2.7% and 4.1%, respectively; 35% relative risk reduction), and death from any cause (5.7% and 8.3%, respectively; 32% relative risk reduction). There was no significant between-group difference in the key secondary outcome (P=0.08 for superiority). Among patients receiving empagliflozin, there was an increased rate of genital infection but no increase in other adverse events. Patients with type 2 diabetes at high risk for cardiovascular events who received empagliflozin, as compared with placebo, had a lower rate of the primary composite cardiovascular outcome and of death from any cause when the study drug was added to standard care. (Funded by Boehringer Ingelheim and Eli Lilly; EMPA-REG OUTCOME ClinicalTrials.gov number, NCT01131676.).

Efficacy and safety of ixekizumab treatment for Japanese patients with moderate to severe plaque psoriasis, erythrodermic psoriasis and generalized pustular psoriasis: Results from a 52-week, open-label, phase 3 study (UNCOVER-J).

PubMed

Saeki, Hidehisa; Nakagawa, Hidemi; Nakajo, Ko; Ishii, Taeko; Morisaki, Yoji; Aoki, Takehiro; Cameron, Gregory S; Osuntokun, Olawale O

2017-04-01

Psoriasis, a chronic, immune-mediated skin disease characterized by red, scaly plaques, affects approximately 0.3% of the population in Japan. The aim of this open-label study was to evaluate the long-term efficacy and safety of ixekizumab, a humanized, anti-interleukin-17A monoclonal antibody, in Japanese patients with plaque psoriasis (n = 78, including 11 psoriatic arthritis), erythrodermic psoriasis (n = 8) and generalized pustular psoriasis (n = 5). Ixekizumab was administrated s.c. at baseline (week 0, 160 mg), from weeks 2 to 12 (80 mg every 2 weeks), and from weeks 16 to 52 (80 mg every 4 weeks). At week 52, 92.3% of patients with plaque psoriasis achieved Psoriasis Area and Severity Index (PASI) 75, 80.8% achieved PASI 90, 48.7% achieved PASI 100, and 52.6% had remission of plaques (by static Physician Global Assessment, sPGA [0]). Difficult to treat areas of psoriasis (nail or scalp) also responded to ixekizumab. All patients with psoriatic arthritis who were assessed (5/5) achieved an American College of Rheumatology 20 response. Most patients with erythrodermic psoriasis or generalized pustular psoriasis responded to ixekizumab and the clinical outcome was maintained over 52 weeks (75% and 60% of patients achieved sPGA [0, 1] at week 52, respectively). Mostly mild or moderate treatment-emergent adverse events were reported by 79 of 91 patients; the most common were nasopharyngitis, eczema, seborrheic dermatitis, urticaria and injection site reactions. In conclusion, 52-week ixekizumab treatment was efficacious and well tolerated in Japanese patients with plaque psoriasis. Efficacy was also observed in patients with erythrodermic psoriasis, generalized pustular psoriasis and psoriatic arthritis. © 2016 Eli Lilly Japan K.K. The Journal of Dermatology published by John Wiley & Sons Australia, Ltd on behalf of Japanese Dermatological Association.

Voyager First Science Meeting

NASA Image and Video Library

2016-10-27

This archival image was released as part of a gallery comparing JPL's past and present, commemorating the 80th anniversary of NASA's Jet Propulsion Laboratory on Oct. 31, 2016. In December 1972, the science steering group for a mission then-known as Mariner Jupiter Saturn 1977 -- later renamed Voyager -- met for the first time at NASA's Jet Propulsion Laboratory in Pasadena, Calif. They are gathered on the steps in front of the administration building (180). The mission was so named because it was planning to send Mariner-class spacecraft to Jupiter and Saturn. It was renamed Voyager a few months before the launch of the twin spacecraft in August and September 1977. This photo shows principal investigators and team leaders for the science experiments and several others from the project and NASA who attended the first meeting. In the first row: Radio Science Subsystem Team Leader Von Eshleman, Project Scientist Edward Stone, Project Manager Harris (Bud) Schurmeier, Mission Analysis and Engineering Manager Ralph Miles, Magnetometer Principal Investigator Norman Ness, NASA Planetary Program Office Deputy Director Ichtiaque Rasool, Robert Soberman (who was proposed to be the principal investigator of the Particulate Matter Investigation, which was not confirmed) and an unidentified member of the NASA Office of Space Science. In the second row: Infrared Interferometer Spectrometer Principal Investigator Rudolf Hanel, Planetary Radio Astronomy Principal Investigator James Warwick, Ultraviolet and Spectrometer Principal Investigator A. Lyle Broadfoot. In the third row: Low-Energy Charged Particles Principal Investigator Stamatios (Tom) Krimigis, Cosmic Ray Subsystem Principal Investigator Rochus (Robbie) Vogt, NASA Outer Planets Missions Program Manager Warren Keller, Imaging Science Subsystem Team Leader Bradford Smith and Photopolarimeter Principal Investigator Charles Lillie. In the fourth row: Plasma Investigation Principal Investigator Herbert Bridge, Spacecraft Systems Manager Raymond Heacock, NASA Outer Planets Missions Program Scientist Milton (Mike) Mitz and Science Manager James Long. http://photojournal.jpl.nasa.gov/catalog/PIA21122

Two-year efficacy and safety of AIR inhaled insulin in patients with type 1 diabetes: An open-label randomized controlled trial.

PubMed

Garg, Satish K; Mathieu, Chantal; Rais, Nadeem; Gao, Haitao; Tobian, Janet A; Gates, Jeffrey R; Ferguson, Jeffrey A; Webb, David M; Berclaz, Pierre-Yves

2009-09-01

Patients with type 1 diabetes require intensive insulin therapy for optimal glycemic control. AIR((R)) inhaled insulin (system from Eli Lilly and Company, Indianapolis, IN) (AIR is a registered trademark of Alkermes, Inc., Cambridge, MA) may be an efficacious and safe alternative to subcutaneously injected (SC) mealtime insulin. This was a Phase 3, 2-year, randomized, open-label, active-comparator, parallel-group study in 385 patients with type 1 diabetes who were randomly assigned to receive AIR insulin or SC insulin (regular human insulin or insulin lispro) at mealtimes. Both groups received insulin glargine once daily. Efficacy measures included mean change in hemoglobin A1C (A1C) from baseline to end point, eight-point self-monitored blood glucose profiles, and insulin dosage. Safety assessments included hypoglycemic events, pulmonary function tests, adverse events, and insulin antibody levels. In both treatment groups, only 20% of subjects reached the target of A1C <7.0%. A significant A1C difference of 0.44% was seen favoring SC insulin, with no difference between the groups in insulin doses or hypoglycemic events at end point. Patients in both treatment groups experienced progressive decreases in lung function, but larger (reversible) decrements in diffusing capacity of the lung for carbon monoxide (DL(CO)) were associated with AIR insulin treatment. Greater weight gain was seen with SC insulin treatment. The AIR inhaled insulin program was terminated by the sponsor prior to availability of any Phase 3 data for reasons unrelated to safety or efficacy. Despite early termination, this trial provides evidence that AIR insulin was less efficacious in lowering A1C and was associated with a greater decrease in DL(CO) and increased incidence of cough than SC insulin in patients with type 1 diabetes.

Does availability of AIR insulin increase insulin use and improve glycemic control in patients with type 2 diabetes?

PubMed

Bergenstal, Richard M; Freemantle, Nick; Leyk, Malgorzata; Cutler, Gordon B; Hayes, Risa P; Muchmore, Douglas B

2009-09-01

In the concordance model, physician and patient discuss treatment options, explore the impact of treatment decisions from the patient's perspective, and make treatment choices together. We tested, in a concordance setting, whether the availability of AIR inhaled insulin (developed by Alkermes, Inc. [Cambridge, MA] and Eli Lilly and Company [Indianapolis, IN]; AIR is a registered trademark of Alkermes, Inc.), as compared with existing treatment options alone, leads to greater initiation and maintenance of insulin therapy and improves glycemic control in patients with type 2 diabetes. This was a 9-month, multicenter, parallel, open-label study in adult, nonsmoking patients with diabetes not optimally controlled by two or more oral antihyperglycemic medications. Patients were randomized to the Standard Options group (n = 516), in which patients chose a regimen from drugs in each major treatment class excluding inhaled insulin, or the Standard Options + AIR insulin group (n = 505), in which patients had the same choices plus AIR insulin. The primary end points were the proportion of patients in each group using insulin at end point and change in hemoglobin A1C (A1C) from baseline to end point. At end point, 53% of patients in the Standard Options group and 59% in the Standard Options + AIR insulin group were using insulin (P = 0.07). Both groups reduced A1C by about 1.2% and reported increased well-being and treatment satisfaction. The most common adverse event with AIR insulin was transient cough. The opportunity to choose AIR insulin did not affect overall use of insulin at end point or A1C outcomes. Regardless of group assignment, utilizing a shared decision-making approach to treatment choices (concordance model), resulted in improved treatment satisfaction and A1C values at end point. Therefore, increasing patient involvement in treatment decisions may improve outcomes.

Comparison of prandial AIR inhaled insulin alone to intensified insulin glargine alone and to AIR insulin plus intensified insulin glargine in patients with type 2 diabetes previously treated with once-daily insulin glargine.

PubMed

Rosenstock, Julio; Eliaschewitz, Freddy G; Heilmann, Cory R; Muchmore, Douglas B; Hayes, Risa P; Belin, Ruth M

2009-09-01

Patients with type 2 diabetes often initiate insulin with once-daily basal insulin. Over time, many patients intensify their insulin regimens in an attempt to attain and sustain glycemic targets. This study compares three intensification approaches: changing insulin glargine to preprandial AIR inhaled insulin (developed by Alkermes, Inc. [Cambridge, MA] and Eli Lilly and Company [Indianapolis, IN]; AIR is a registered trademark of Alkermes, Inc.), intensifying glargine via validated titration algorithms (IG), or adding AIR insulin while intensifying glargine (AIR + IG). Five hundred sixty patients with hemoglobin A(1c) (A1C) of 7.5-10.5%, on one or more antihyperglycemic medications, and on once-daily insulin glargine for > or =4 months were randomly allocated to one of the three treatments lasting 52 weeks. The primary objective assessed between-group differences in A1C mean change from baseline to 24 weeks using last-observation-carried-forward (LOCF) in the intent-to-treat population. At 24 weeks, A1C was reduced from a mean baseline of 8.5% to 7.7%, 7.9%, and 7.5% for the AIR, IG, and AIR + IG groups, respectively. AIR produced 0.20% greater A1C decrease than IG (least-squares mean difference = -0.20%; 95% confidence interval [CI], -0.39, -0.02). AIR + IG had a 0.35% greater A1C decrease versus IG (95% CI, -0.57, -0.13). The -0.15% difference between AIR + IG versus AIR was not significant (P < 0.198). More hypoglycemia categorized as severe occurred with AIR alone versus IG alone at LOCF end points. More nocturnal hypoglycemia occurred with IG alone versus AIR alone and AIR + IG. Preprandial inhaled insulin provides an alternative for patients not optimized on insulin glargine alone. Glycemic control, hypoglycemic risk, delivery preference, and regimen complexity must be considered when selecting insulin initiation and optimization regimens.

Olaratumab in Combination with Doxorubicin for the Treatment of Advanced Soft Tissue Sarcoma: An Evidence Review Group Perspective of a National Institute for Health and Care Excellence Single Technology Appraisal.

PubMed

Tikhonova, Irina A; Jones-Hughes, Tracey; Dunham, James; Warren, Fiona C; Robinson, Sophie; Stephens, Peter; Hoyle, Martin

2018-01-01

The manufacturer of olaratumab (Lartruvo ® ), Eli Lilly & Company Limited, submitted evidence for the clinical and cost effectiveness of this drug, in combination with doxorubicin, for untreated advanced soft tissue sarcoma (STS) not amenable to surgery or radiotherapy, as part of the National Institute for Health and Care Excellence (NICE) Single Technology Appraisal process. The Peninsula Technology Assessment Group, commissioned to act as the Evidence Review Group (ERG), critically reviewed the company's submission. Clinical effectiveness evidence for the company's analysis was derived from an open-label, randomised controlled trial, JGDG. The analysis was based on a partitioned survival model with a time horizon of 25 years, and the perspective was of the UK National Health Service (NHS) and Personal Social Services. Costs and benefits were discounted at 3.5% per year. Given the available evidence, olaratumab is likely to meet NICE's end-of-life criteria. To improve the cost effectiveness of olaratumab, the company offered a discount through a Commercial Access Agreement (CAA) with the NHS England. When the discount was applied, the mean base-case and probabilistic incremental cost-effectiveness ratios (ICERs) for olaratumab plus doxorubicin versus the standard-of-care doxorubicin were £46,076 and £47,127 per quality-adjusted life-year (QALY) gained, respectively; the probability of this treatment being cost effective at the willingness-to-pay threshold of £50,000 per QALY gained, applicable to end-of-life treatments, was 0.54. The respective ICERs from the ERG's analysis were approximately £60,000/QALY gained, and the probability of the treatment being cost effective was 0.21. In August 2017, the NICE Appraisal Committee recommended olaratumab in combination with doxorubicin for this indication for use via the UK Cancer Drugs Fund under the agreed CAA until further evidence being collected in the ongoing phase III trial-ANNOUNCE-becomes available in December 2020.

Study protocol: systematic review and meta-analysis of randomized controlled trials in first-line treatment of squamous non-small cell lung cancer

PubMed Central

2014-01-01

Background There is a high unmet need for effective treatments for patients with squamous non-small cell lung cancer (NSCLC). Eli Lilly and Company is conducting a phase III, randomized, multicenter, open-label study of gemcitabine plus cisplatin plus necitumumab (GC + N) versus gemcitabine plus cisplatin (GC) for the first-line treatment of patients with stage IV squamous NSCLC. Given GC is not the only treatment commonly used for the treatment of squamous NSCLC, this study was designed to compare the survival, toxicity, and quality of life outcomes of current treatment strategies for squamous NSCLC in the first-line setting. Methods/Design A systematic review and meta-analysis (including indirect comparisons) of treatments used in squamous NSCLC will be conducted to assess the clinical efficacy (overall and progression-free survival), health-related quality of life (HRQoL), and safety (grade 3–4 toxicity) of GC + N compared to other treatments used in squamous NSCLC. PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines will be followed for all aspects of this study. A systematic literature review will be conducted to identify randomized controlled trials evaluating chemotherapy treatment in first-line NSCLC. Eligible articles will be restricted to randomized controlled trials (RCTs) among chemotherapy-naïve advanced NSCLC cancer patients that report outcome data (survival, toxicity, or quality of life) for patients with squamous histology. Following data extraction and validation, data consistency and study heterogeneity will be assessed. A network meta-analysis will be conducted based on the available hazard ratios for overall and progression-free survival, odds ratios for published toxicity data, and mean difference of HRQoL scales. Sensitivity analyses will be conducted. Discussion This is a presentation of the study protocol only. Results and conclusions are pending completion of this study. Systematic review registration PROSPERO CRD42014008968 PMID:25227571

Behaviours, thoughts and perceptions around mealtime insulin usage and wastage among people with type 1 and type 2 diabetes mellitus: A cross-sectional survey study.

PubMed

Van Brunt, Kate; Pedersini, Riccardo; Rooney, Jillian; Corrigan, Sheila M

2017-04-01

People with diabetes who use mealtime insulin (MTI) were surveyed about insulin wastage and injection habits when insufficient insulin remains in a disposable prefilled pen/cartridge to administer a full dose in a single injection. Cross-sectional, online, self-reported survey of MTI usage/wastage behaviour in 400 adults with type 1 (n=120) or type 2 (n=280) diabetes mellitus administering >20units/day of MTI via 100units/ml prefilled pens/cartridges for ⩾1month, conducted in France, Germany, Italy and UK. Participants' mean±standard deviation age was 54.5±12.2years, body mass index was 29.9±7.2kg/m 2 and duration of MTI therapy was 8.6±7.8years. They administered 3.7±5.9 injections/day with meals, using 11.3±18.0 prefilled pens/cartridges per month. Overall, 63.5% split the dose across two prefilled pens/cartridges (i.e. administered two injections to obtain a full dose), 15.0% used just what remained in their current pen (i.e. took a lower-than-prescribed dose) and 36.3% discarded prefilled pens/cartridges still containing insulin (i.e. took full dose with new pen). The latter participants discarded a mean 5.5±8.2 prefilled pens/cartridges monthly still containing insulin, each containing 8.6±8.7 units of insulin. Participants who wasted insulin considered it frustrating, time-consuming and painful to inject twice. Patients taking >20units/day MTI can find transitions between insulin pens challenging. This study highlights the need to identify ways of improving transitions between pens to make transitions easier for insulin users, which could potentially improve adherence to prescribed doses and reduce waste. Copyright © 2016 Eli Lilly and Company. Published by Elsevier B.V. All rights reserved.

Baricitinib in Patients with Rheumatoid Arthritis and an Inadequate Response to Conventional Disease-Modifying Antirheumatic Drugs in United States and Rest of World: A Subset Analysis.

PubMed

Wells, Alvin F; Greenwald, Maria; Bradley, John D; Alam, Jahangir; Arora, Vipin; Kartman, Cynthia E

2018-06-01

This article evaluates the efficacy and safety of baricitinib 4 mg versus placebo in United States including Puerto Rico (US) and rest of the world (ROW) subpopulations using data pooled from RA-BEAM and RA-BUILD, which enrolled patients with moderate-to-severe adult-onset rheumatoid arthritis (RA). In RA-BEAM, patients with an inadequate response (IR) to methotrexate, at least one X-ray erosion, and high sensitivity C-reactive protein (hsCRP) ≥ 6 mg/L were randomized to placebo or orally administered baricitinib 4 mg daily or subcutaneously administered adalimumab 40 mg every other week. In RA-BUILD, patients with an IR to at least one conventional synthetic disease-modifying antirheumatic drug (csDMARD) and with hsCRP ≥ 3.6 mg/L were randomized to placebo or baricitinib 2 or 4 mg daily. Patients in both trials were biologic naive. In this post hoc analysis, data from both studies were pooled (714 baricitinib 4 mg-treated, 716 placebo-treated patients). Overall, 188 US and 1242 ROW patients were included. Subgroups differed in baseline characteristics including race, weight, age, time since RA diagnosis, current corticosteroid use, and previous csDMARD use. At weeks 12 and 24, baricitinib-treated patients had larger responses compared to placebo-treated patients for multiple efficacy outcomes: American College of Rheumatology 20/50/70 response, low disease activity, remission, Disease Activity Score 28-C-reactive protein, and Health Assessment Questionnaire-Disability Index. Overall, similar efficacy was observed in US and ROW subgroups with no notable safety differences between subgroups at weeks 12 or 24. Baricitinib 4 mg was efficacious compared to placebo in US and ROW subpopulations. Safety was similar between subgroups. Eli Lilly & Company and Incyte Corporation. ClinicalTrials.gov identifiers, NCT01721057; NCT01710358.

Evacetrapib and Cardiovascular Outcomes in High-Risk Vascular Disease.

PubMed

Lincoff, A Michael; Nicholls, Stephen J; Riesmeyer, Jeffrey S; Barter, Philip J; Brewer, H Bryan; Fox, Keith A A; Gibson, C Michael; Granger, Christopher; Menon, Venu; Montalescot, Gilles; Rader, Daniel; Tall, Alan R; McErlean, Ellen; Wolski, Kathy; Ruotolo, Giacomo; Vangerow, Burkhard; Weerakkody, Govinda; Goodman, Shaun G; Conde, Diego; McGuire, Darren K; Nicolau, Jose C; Leiva-Pons, Jose L; Pesant, Yves; Li, Weimin; Kandath, David; Kouz, Simon; Tahirkheli, Naeem; Mason, Denise; Nissen, Steven E

2017-05-18

The cholesteryl ester transfer protein inhibitor evacetrapib substantially raises the high-density lipoprotein (HDL) cholesterol level, reduces the low-density lipoprotein (LDL) cholesterol level, and enhances cellular cholesterol efflux capacity. We sought to determine the effect of evacetrapib on major adverse cardiovascular outcomes in patients with high-risk vascular disease. In a multicenter, randomized, double-blind, placebo-controlled phase 3 trial, we enrolled 12,092 patients who had at least one of the following conditions: an acute coronary syndrome within the previous 30 to 365 days, cerebrovascular atherosclerotic disease, peripheral vascular arterial disease, or diabetes mellitus with coronary artery disease. Patients were randomly assigned to receive either evacetrapib at a dose of 130 mg or matching placebo, administered daily, in addition to standard medical therapy. The primary efficacy end point was the first occurrence of any component of the composite of death from cardiovascular causes, myocardial infarction, stroke, coronary revascularization, or hospitalization for unstable angina. At 3 months, a 31.1% decrease in the mean LDL cholesterol level was observed with evacetrapib versus a 6.0% increase with placebo, and a 133.2% increase in the mean HDL cholesterol level was seen with evacetrapib versus a 1.6% increase with placebo. After 1363 of the planned 1670 primary end-point events had occurred, the data and safety monitoring board recommended that the trial be terminated early because of a lack of efficacy. After a median of 26 months of evacetrapib or placebo, a primary end-point event occurred in 12.9% of the patients in the evacetrapib group and in 12.8% of those in the placebo group (hazard ratio, 1.01; 95% confidence interval, 0.91 to 1.11; P=0.91). Although the cholesteryl ester transfer protein inhibitor evacetrapib had favorable effects on established lipid biomarkers, treatment with evacetrapib did not result in a lower rate of cardiovascular events than placebo among patients with high-risk vascular disease. (Funded by Eli Lilly; ACCELERATE ClinicalTrials.gov number, NCT01687998 .).

The novel functions of cGMP-specific phosphodiesterase 5 and its inhibitors in carcinoma cells and pulmonary/cardiovascular vessels.

PubMed

Zhu, Bing; Strada, Samuel J

2007-01-01

PDE5 is a key enzyme involved in the regulation of cGMP-specific signaling pathways in normal physiological processes such as smooth muscle contraction and relaxation. For this reason, inhibition of the enzyme can alter those pathophysiological conditions associated with a lowering cGMP level in tissues. For example, selective PDE5 inhibitors, such as sildenafil (Viagra, Pfizer), tadalafil (Cialis, Lilly-ICOS), and vardenafil (Levitra, Bayer), have been successfully used to treat the condition of human erectile dysfunction. More recently, the involvement of this enzyme has been proposed to influence antiproliferation and proapoptotic mechanism in multiple carcinomas. The data supporting this idea is based on increases in PDE5 activities in many carcinomas and the ability of PDE5 inhibitors such as exisulind and its analogs related to anticancer activities. Inhibition of PDE5 that results in sustained increases in [cGMP](i) are required to modify the process of apoptosis and mitotic arrest in those carcinoma cells with enhanced PDE5 expressions. Increases in PDE5 are also involved in contributing to the pathological changes in the pulmonary system resulting in hyper-proliferative remodeling of both smooth muscle and endothelium in models of pulmonary hypertension. For this reason, the use of PDE5 inhibitors in the treatment of human pulmonary hypertension has met with some success. The differences that we have previously noted in PDE isoenzymes in pulmonary arterial and microvascular endothelial cells may provide a more selective cellular strategy for use of such inhibitor. Additional studies on structure biology of these enzymes should lead to the development of agents with better cellular specificity than currently available drugs. Considering the enormous progress that has been made in the last few years, the future looks promising for agents affecting this enzyme and related systems.

Drotrecogin alfa (activated) in adults with septic shock.

PubMed

Ranieri, V Marco; Thompson, B Taylor; Barie, Philip S; Dhainaut, Jean-François; Douglas, Ivor S; Finfer, Simon; Gårdlund, Bengt; Marshall, John C; Rhodes, Andrew; Artigas, Antonio; Payen, Didier; Tenhunen, Jyrki; Al-Khalidi, Hussein R; Thompson, Vivian; Janes, Jonathan; Macias, William L; Vangerow, Burkhard; Williams, Mark D

2012-05-31

There have been conflicting reports on the efficacy of recombinant human activated protein C, or drotrecogin alfa (activated) (DrotAA), for the treatment of patients with septic shock. In this randomized, double-blind, placebo-controlled, multicenter trial, we assigned 1697 patients with infection, systemic inflammation, and shock who were receiving fluids and vasopressors above a threshold dose for 4 hours to receive either DrotAA (at a dose of 24 μg per kilogram of body weight per hour) or placebo for 96 hours. The primary outcome was death from any cause 28 days after randomization. At 28 days, 223 of 846 patients (26.4%) in the DrotAA group and 202 of 834 (24.2%) in the placebo group had died (relative risk in the DrotAA group, 1.09; 95% confidence interval [CI], 0.92 to 1.28; P=0.31). At 90 days, 287 of 842 patients (34.1%) in the DrotAA group and 269 of 822 (32.7%) in the placebo group had died (relative risk, 1.04; 95% CI, 0.90 to 1.19; P=0.56). Among patients with severe protein C deficiency at baseline, 98 of 342 (28.7%) in the DrotAA group had died at 28 days, as compared with 102 of 331 (30.8%) in the placebo group (risk ratio, 0.93; 95% CI, 0.74 to 1.17; P=0.54). Similarly, rates of death at 28 and 90 days were not significantly different in other predefined subgroups, including patients at increased risk for death. Serious bleeding during the treatment period occurred in 10 patients in the DrotAA group and 8 in the placebo group (P=0.81). DrotAA did not significantly reduce mortality at 28 or 90 days, as compared with placebo, in patients with septic shock. (Funded by Eli Lilly; PROWESS-SHOCK ClinicalTrials.gov number, NCT00604214.).

ERCC1 isoform expression and DNA repair in non-small-cell lung cancer.

PubMed

Friboulet, Luc; Olaussen, Ken André; Pignon, Jean-Pierre; Shepherd, Frances A; Tsao, Ming-Sound; Graziano, Stephen; Kratzke, Robert; Douillard, Jean-Yves; Seymour, Lesley; Pirker, Robert; Filipits, Martin; André, Fabrice; Solary, Eric; Ponsonnailles, Florence; Robin, Angélique; Stoclin, Annabelle; Dorvault, Nicolas; Commo, Frédéric; Adam, Julien; Vanhecke, Elsa; Saulnier, Patrick; Thomale, Jürgen; Le Chevalier, Thierry; Dunant, Ariane; Rousseau, Vanessa; Le Teuff, Gwénaël; Brambilla, Elisabeth; Soria, Jean-Charles

2013-03-21

The excision repair cross-complementation group 1 (ERCC1) protein is a potential prognostic biomarker of the efficacy of cisplatin-based chemotherapy in non-small-cell lung cancer (NSCLC). Although several ongoing trials are evaluating the level of expression of ERCC1, no consensus has been reached regarding a method for evaluation. We used the 8F1 antibody to measure the level of expression of ERCC1 protein by means of immunohistochemical analysis in a validation set of samples obtained from 494 patients in two independent phase 3 trials (the National Cancer Institute of Canada Clinical Trials Group JBR.10 and the Cancer and Leukemia Group B 9633 trial from the Lung Adjuvant Cisplatin Evaluation Biology project). We compared the results of repeated staining of the entire original set of samples obtained from 589 patients in the International Adjuvant Lung Cancer Trial Biology study, which had led to the initial correlation between the absence of ERCC1 expression and platinum response, with our previous results in the same tumors. We mapped the epitope recognized by 16 commercially available ERCC1 antibodies and investigated the capacity of the different ERCC1 isoforms to repair platinum-induced DNA damage. We were unable to validate the predictive effect of immunostaining for ERCC1 protein. The discordance in the results of staining for ERCC1 suggested a change in the performance of the 8F1 antibody since 2006. We found that none of the 16 antibodies could distinguish among the four ERCC1 protein isoforms, whereas only one isoform produced a protein that had full capacities for nucleotide excision repair and cisplatin resistance. Immunohistochemical analysis with the use of currently available ERCC1 antibodies did not specifically detect the unique functional ERCC1 isoform. As a result, its usefulness in guiding therapeutic decision making is limited. (Funded by Eli Lilly and others.).

Impact of Proton Pump Inhibitor Use on the Comparative Effectiveness and Safety of Prasugrel Versus Clopidogrel: Insights From the Treatment With Adenosine Diphosphate Receptor Inhibitors: Longitudinal Assessment of Treatment Patterns and Events After Acute Coronary Syndrome (TRANSLATE-ACS) Study.

PubMed

Jackson, Larry R; Peterson, Eric D; McCoy, Lisa A; Ju, Christine; Zettler, Marjorie; Baker, Brian A; Messenger, John C; Faries, Douglas E; Effron, Mark B; Cohen, David J; Wang, Tracy Y

2016-10-21

Proton pump inhibitors (PPIs) reduce gastrointestinal bleeding events but may alter clopidogrel metabolism. We sought to understand the comparative effectiveness and safety of prasugrel versus clopidogrel in the context of proton pump inhibitor (PPI) use. Using data on 11 955 acute myocardial infarction (MI) patients treated with percutaneous coronary intervention at 233 hospitals and enrolled in the TRANSLATE-ACS study, we compared whether discharge PPI use altered the association of 1-year adjusted risks of major adverse cardiovascular events (MACE; death, MI, stroke, or unplanned revascularization) and Global Use of Strategies To Open Occluded Arteries (GUSTO) moderate/severe bleeding between prasugrel- and clopidogrel-treated patients. Overall, 17% of prasugrel-treated and 19% of clopidogrel-treated patients received a PPI at hospital discharge. At 1 year, patients discharged on a PPI versus no PPI had higher risks of MACE (adjusted hazard ratio [HR] 1.38, 95% confidence interval [CI] 1.21-1.58) and GUSTO moderate/severe bleeding (adjusted HR 1.55, 95% CI 1.15-2.09). Risk of MACE was similar between prasugrel and clopidogrel regardless of PPI use (adjusted HR 0.88, 95% CI 0.62-1.26 with PPI, adjusted HR 1.07, 95% CI 0.90-1.28 without PPI, interaction P=0.31). Comparative bleeding risk associated with prasugrel versus clopidogrel use differed based on PPI use but did not reach statistical significance (adjusted HR 0.73, 95% CI 0.36-1.48 with PPI, adjusted HR 1.34, 95% CI 0.79-2.27 without PPI, interaction P=0.17). PPIs did not significantly affect the MACE and bleeding risk associated with prasugrel use, relative to clopidogrel. URL: https://www.clinicaltrials.gov. Unique identifier: NCT01088503. © 2016 The Authors and Eli Lilly & Company. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

[Telemedicine in the ICU - the possibilities and limitations of an innovation].

PubMed

Deisz, R; Marx, G

2016-11-01

Intensive care medicine is challenged by demographic changes and an increasing number of patient combined with existing shortage of doctors. Telemedicine is a promising approach to ensure patient care in the coming years. Due to a shortage of intensive care physicians in the USA, comprehensive telemedicine coverage has already been established. To date, 11 % of all hospitals are supported by a telemedicine center. The beneficial impact in terms of quality of care, patient safety and economic factors has been confirmed in numerous multicenter studies. In the largest multicenter study by Lilly et al., including 107,432 critically ill patients in the intervention group, telemedicine interventions led to a reduced ICU and hospital mortality. In addition, tele-consulting significantly reduced the ICU- and hospital length of stay. These findings were further supported by following studies and metaanalysis, which confirmed these results. The incidence of ventilator-associated pneumonia and catheter-associated infections was significantly reduced, when compared to the preintervention group. Furthermore, patient safety and treatment outcomes were improved by increased guideline adherence. Last, the telemedicine intervention significantly decreased the overall treatment costs. These positive results were reproducible even in larger and academic hospitals. At the same time it should be pointed out that a transfer to other health care systems should be considered cautiously in the context of different local infrastructure and culture. Finally, it has to be investigated to what extent the results can be transferred to the health-care situation in Germany. Previous data demonstrated that telemedical support can improve the outcome in critically ill patients, both during hospitalization as well as in the long-term result until the discharge home. Telemedicine is neither a magic bullet nor a replacement for a physician. Instead it is a new type of medical cooperation to further improve the outcomes of critically ill patients.

Numerical Studies of Flow Past Two Side-by-Side Circular Cylinders

NASA Astrophysics Data System (ADS)

Shao, J.; Zhang, C.

Multiple circular cylindrical configurations are widely used in engineering applications. The fluid dynamics of the flow around two identical circular cylinders in side-by-side arrangement has been investigated by both experiments and numerical simulations. The center-to-center transverse pitch ratio T/D plays an important role in determining the flow features. It is observed that for 1 < T/D < 1.1 to 1.2, a single vortex street is formed; for 1.2< T/D < 2 to 2.2, bi-stable narrow and wide wakes are formed; for 2.7< T/D < 4 or 5, anti-phase or in-phase vortex streets are formed. In the current study, the vortex structures of turbulent flows past two slightly heated side-by-side circular cylinders are investigated employing the large eddy simulation (LES). Simulations are performed using a commercial CFD software, FLUENT. The Smagorinsky-Lilly subgrid-scale model is employed for the large eddy simulation. The Reynolds number based on free-stream velocity and cylinder diameter is 5 800, which is in the subcritical regime. The transverse pitch ratio T/D = 3 is investigated. Laminar boundary layer, transition in shear layer, flow separation, large vortex structures and flow interference in the wake are all involved in the flow. Such complex flow features make the current study a challenging task. Both flow field and temperature field are investigated. The calculated results are analyzed and compared with experimental data. The simulation results are qualitatively in accordance with experimental observations. Two anti-phase vortex streets are obtained by the large-eddy simulation, which agrees with the experimental observation. At this transverse pitch ratio, these two cylinders behave as independent, isolated single cylinder in cross flow. The time-averaged streamwise velocity and temperature at x/D=10 are in good agreement with the experimental data. Figure1 displays the instantaneous spanwise vorticity at the center plane.

[The register GiViTI about the use of the drug Xigris® in the Italian intensive care units].

PubMed

Rossi, Carlotta; Giardino, Michele; Crespi, Daniele; Anghileri, Abramo; Poole, Daniele; Bertolini, Guido

2013-06-01

The Register was aimed at monitoring the use, possible side effects, and clinical effectiveness of Xigris® - drotrecogin alfa (activated) - for the treatment of severe sepsis in Italian intensive care units (ICUs). Data collection was performed using an online web form or a specific electronic module of the software Margherita, available only for the ICUs adhering to the GiViTI. Drug purchase information available for each center was used to identify and stimulate collaboration of non-compliant centers. Several countermeasures were taken to have the largest participation. We analyzed data from 1001 patients treated in 161 ICUs between July 2003 and September 2007, corresponding to 70% of all the patients who received the drug in that period. The off-label use of the drug was frequent: 15.6% of cases before and 27.3% after the label change with the introduction of timing restrictions. Treatment was temporarily interrupted in 10%, and definitely stopped in 25% of cases, after the occurrence of adverse events, the most frequent being bleeding. Severe bleeding occurred in 3.8% of patients. Multivariable analysis, which allowed an adjusted comparison with a control group, showed that treatment increased mortality among elective-surgery patients (OR 2.79, 95%CI 1.31-5.97). The results of this study and other evidences led the European Medicines Agency (EMA) to require a confirmatory trial in 2007. In October 2011 Ely-Lilly, the producer of the drug, announced the worldwide withdrawal from the market of Xigris®, on the basis of the negative results of the confirmatory trial. The availability of purchase information is essential to carry out post-marketing drug surveillance studies, since it allows to identify and contact non-compliant centers. Actually, a representative sample of treated patients provides reliable information on the use, efficacy, and safety of the drug in daily clinical practice that could positively influence healthcare policies.

A breakthrough in enzyme technology to fight penicillin resistance-industrial application of penicillin amidase.

PubMed

Buchholz, Klaus

2016-05-01

Enzymatic penicillin hydrolysis by penicillin amidase (also penicillin acylase, PA) represents a Landmark: the first industrially and economically highly important process using an immobilized biocatalyst. Resistance of infective bacteria to antibiotics had become a major topic of research and industrial activities. Solutions to this problem, the antibiotics resistance of infective microorganisms, required the search for new antibiotics, but also the development of derivatives, notably penicillin derivatives, that overcame resistance. An obvious route was to hydrolyse penicillin to 6-aminopenicillanic acid (6-APA), as a first step, for the introduction via chemical synthesis of various different side chains. Hydrolysis via chemical reaction sequences was tedious requiring large amounts of toxic chemicals, and they were cost intensive. Enzymatic hydrolysis using penicillin amidase represented a much more elegant route. The basis for such a solution was the development of techniques for enzyme immobilization, a highly difficult task with respect to industrial application. Two pioneer groups started to develop solutions to this problem in the late 1960s and 1970s: that of Günter Schmidt-Kastner at Bayer AG (Germany) and that of Malcolm Lilly of Imperial College London. Here, one example of this development, that at Bayer, will be presented in more detail since it illustrates well the achievement of a solution to the problems of industrial application of enzymatic processes, notably development of an immobilization method for penicillin amidase suitable for scale up to application in industrial reactors under economic conditions. A range of bottlenecks and technical problems of large-scale application had to be overcome. Data giving an inside view of this pioneer achievement in the early phase of the new field of biocatalysis are presented. The development finally resulted in a highly innovative and commercially important enzymatic process to produce 6-APA that created a new antibiotics industry and that opened the way for the establishment of over 100 industrial processes with immobilized biocatalysts worldwide today.

Variability in P-Glycoprotein Inhibitory Potency (IC50) Using Various in Vitro Experimental Systems: Implications for Universal Digoxin Drug-Drug Interaction Risk Assessment Decision Criteria

PubMed Central

Bentz, Joe; O’Connor, Michael P.; Bednarczyk, Dallas; Coleman, JoAnn; Lee, Caroline; Palm, Johan; Pak, Y. Anne; Perloff, Elke S.; Reyner, Eric; Balimane, Praveen; Brännström, Marie; Chu, Xiaoyan; Funk, Christoph; Guo, Ailan; Hanna, Imad; Herédi-Szabó, Krisztina; Hillgren, Kate; Li, Libin; Hollnack-Pusch, Evelyn; Jamei, Masoud; Lin, Xuena; Mason, Andrew K.; Neuhoff, Sibylle; Patel, Aarti; Podila, Lalitha; Plise, Emile; Rajaraman, Ganesh; Salphati, Laurent; Sands, Eric; Taub, Mitchell E.; Taur, Jan-Shiang; Weitz, Dietmar; Wortelboer, Heleen M.; Xia, Cindy Q.; Xiao, Guangqing; Yabut, Jocelyn; Yamagata, Tetsuo; Zhang, Lei

2013-01-01

A P-glycoprotein (P-gp) IC50 working group was established with 23 participating pharmaceutical and contract research laboratories and one academic institution to assess interlaboratory variability in P-gp IC50 determinations. Each laboratory followed its in-house protocol to determine in vitro IC50 values for 16 inhibitors using four different test systems: human colon adenocarcinoma cells (Caco-2; eleven laboratories), Madin-Darby canine kidney cells transfected with MDR1 cDNA (MDCKII-MDR1; six laboratories), and Lilly Laboratories Cells—Porcine Kidney Nr. 1 cells transfected with MDR1 cDNA (LLC-PK1-MDR1; four laboratories), and membrane vesicles containing human P-glycoprotein (P-gp; five laboratories). For cell models, various equations to calculate remaining transport activity (e.g., efflux ratio, unidirectional flux, net-secretory-flux) were also evaluated. The difference in IC50 values for each of the inhibitors across all test systems and equations ranged from a minimum of 20- and 24-fold between lowest and highest IC50 values for sertraline and isradipine, to a maximum of 407- and 796-fold for telmisartan and verapamil, respectively. For telmisartan and verapamil, variability was greatly influenced by data from one laboratory in each case. Excluding these two data sets brings the range in IC50 values for telmisartan and verapamil down to 69- and 159-fold. The efflux ratio-based equation generally resulted in severalfold lower IC50 values compared with unidirectional or net-secretory-flux equations. Statistical analysis indicated that variability in IC50 values was mainly due to interlaboratory variability, rather than an implicit systematic difference between test systems. Potential reasons for variability are discussed and the simplest, most robust experimental design for P-gp IC50 determination proposed. The impact of these findings on drug-drug interaction risk assessment is discussed in the companion article (Ellens et al., 2013) and recommendations are provided. PMID:23620485

Assay development and case history of a 32K-biased library high-content MK2-EGFP translocation screen to identify p38 mitogen-activated protein kinase inhibitors on the ArrayScan 3.1 imaging platform.

PubMed

Trask, Oscar J; Baker, Audrey; Williams, Rhonda Gates; Nickischer, Debra; Kandasamy, Ramani; Laethem, Carmen; Johnston, Patricia A; Johnston, Paul A

2006-01-01

This chapter describes the conversion and assay development of a 96-well MK2-EGFP translocation assay into a higher density 384-well format high-content assay to be screened on the ArrayScan 3.1 imaging platform. The assay takes advantage of the well-substantiated hypothesis that mitogen-activated protein kinase-activating protein kinase-2 (MK2) is a substrate of p38 MAPK kinase and that p38-induced phosphorylation of MK-2 induces a nucleus-to-cytoplasm translocation. This chapter also presents a case history of the performance of the MK2-EGFP translocation assay, run as a "high-content" screen of a 32K kinase-biased library to identify p38 inhibitors. The assay performed very well and a number of putative p38 inhibitor hits were identified. Through the use of multiparameter data provided by the nuclear translocation algorithm and by checking images, a number of compounds were identified that were potential artifacts due to interference with the imaging format. These included fluorescent compounds, or compounds that dramatically reduced cell numbers due to cytotoxicity or by disrupting cell adherence. A total of 145 compounds produced IC(50) values <50.0 muM in the MK2-EGFP translocation assay, and a cross target query of the Lilly-RTP HTS database confirmed their inhibitory activity against in vitro kinase targets, including p38a. Compounds were confirmed structurally by LCMS analysis and profiled in cell-based imaging assays for MAPK signaling pathway selectivity. Three of the hit scaffolds identified in the MK2-EGFP translocation HCS run on the ArrayScan were selected for a p38a inhibitor hit-to-lead structure activity relationship (SAR) chemistry effort.

Quantifying the chiral magnetic effect from anomalous-viscous fluid dynamics

NASA Astrophysics Data System (ADS)

Jiang, Yin; Shi, Shuzhe; Yin, Yi; Liao, Jinfeng

2018-01-01

The Chiral Magnetic Effect (CME) is a macroscopic manifestation of fundamental chiral anomaly in a many-body system of chiral fermions, and emerges as an anomalous transport current in the fluid dynamics framework. Experimental observation of the CME is of great interest and has been reported in Dirac and Weyl semimetals. Significant efforts have also been made to look for the CME in heavy ion collisions. Critically needed for such a search is the theoretical prediction for the CME signal. In this paper we report a first quantitative modeling framework, Anomalous Viscous Fluid Dynamics (AVFD), which computes the evolution of fermion currents on top of realistic bulk evolution in heavy ion collisions and simultaneously accounts for both anomalous and normal viscous transport effects. AVFD allows a quantitative understanding of the generation and evolution of CME-induced charge separation during the hydrodynamic stage, as well as its dependence on theoretical ingredients. With reasonable estimates of key parameters, the AVFD simulations provide the first phenomenologically successful explanation of the measured signal in 200 AGeV AuAu collisions. This material is based upon work supported by the U.S. Department of Energy, Office of Science, Office of Nuclear Physics, within the framework of the Beam Energy Scan Theory (BEST) Topical Collaboration. The work is also supported in part by the National Science Foundation under Grant No. PHY-1352368 (SS and JL), by the National Science Foundation of China under Grant No. 11735007 (JL) and by the U.S. Department of Energy under grant Contract Number No. DE- SC0012704 (BNL)/DE-SC0011090 (MIT) (YY). JL is grateful to the Institute for Nuclear Theory for hospitality during the INT-16-3 Program. The computation of this research was performed on IU’s Big Red II cluster, supported in part by Lilly Endowment, Inc. (through its support for the Indiana University Pervasive Technology Institute) and in part by the Indiana METACyt Initiative.

Application of artificial neural network to predict clay sensitivity in a high landslide prone area using CPTu data- A case study in Southwest of Sweden

NASA Astrophysics Data System (ADS)

Shahri, Abbas; Mousavinaseri, Mahsasadat; Naderi, Shima; Espersson, Maria

2015-04-01

Application of Artificial Neural Networks (ANNs) in many areas of engineering, in particular to geotechnical engineering problems such as site characterization has demonstrated some degree of success. The present paper aims to evaluate the feasibility of several various types of ANN models to predict the clay sensitivity of soft clays form piezocone penetration test data (CPTu). To get the aim, a research database of CPTu data of 70 test points around the Göta River near the Lilli Edet in the southwest of Sweden which is a high prone land slide area were collected and considered as input for ANNs. For training algorithms the quick propagation, conjugate gradient descent, quasi-Newton, limited memory quasi-Newton and Levenberg-Marquardt were developed tested and trained using the CPTu data to provide a comparison between the results of field investigation and ANN models to estimate the clay sensitivity. The reason of using the clay sensitivity parameter in this study is due to its relation to landslides in Sweden.A special high sensitive clay namely quick clay is considered as the main responsible for experienced landslides in Sweden which has high sensitivity and prone to slide. The training and testing program was started with 3-2-1 ANN architecture structure. By testing and trying several various architecture structures and changing the hidden layer in order to have a higher output resolution the 3-4-4-3-1 architecture structure for ANN in this study was confirmed. The tested algorithm showed that increasing the hidden layers up to 4 layers in ANN can improve the results and the 3-4-4-3-1 architecture structure ANNs for prediction of clay sensitivity represent reliable and reasonable response. The obtained results showed that the conjugate gradient descent algorithm with R2=0.897 has the best performance among the tested algorithms. Keywords: clay sensitivity, landslide, Artificial Neural Network

Quality control of human tissues--experience from the Indiana University Cancer Center-Lilly Research Labs human tissue bank.

PubMed

Sandusky, George E; Teheny, Katie Heinz; Esterman, Mike; Hanson, Jeff; Williams, Stephen D

2007-01-01

The success of molecular research and its applications in both the clinical and basic research arenas is strongly dependent on the collection, handling, storage, and quality control of fresh human tissue samples. This tissue bank was set up to bank fresh surgically obtained human tissue using a Clinical Annotated Tissue Database (CATD) in order to capture the associated patient clinical data and demographics using a one way patient encryption scheme to protect patient identification. In this study, we determined that high quality of tissue samples is imperative for both genomic and proteomic molecular research. This paper also contains a brief compilation of the literature involved in the patient ethics, patient informed consent, patient de-identification, tissue collection, processing, and storage as well as basic molecular research generated from the tissue bank using good clinical practices. The current applicable rules, regulations, and guidelines for handling human tissues are briefly discussed. More than 6,610 cancer patients have been consented (97% of those that were contacted by the consenter) and 16,800 tissue specimens have been banked from these patients in 9 years. All samples collected in the bank were QC'd by a pathologist. Approximately 1,550 tissue samples have been requested for use in basic, clinical, and/or biomarker cancer research studies. Each tissue aliquot removed from the bank for a research study were evaluated by a second H&E, if the samples passed the QC, they were submitted for genomic and proteomic molecular analysis/study. Approximately 75% of samples evaluated were of high histologic quality and used for research studies. Since 2003, we changed the patient informed consent to allow the tissue bank to gather more patient clinical follow-up information. Ninety two percent of the patients (1,865 patients) signed the new informed consent form and agreed to be re-contacted for follow-up information on their disease state. In addition, eighty five percent of patients (1,584) agreed to be re-contacted to provide a biological fluid sample to be used for biomarker research.

Administration of human recombinant activated protein C is not associated with pancreatic parenchymal haemorrhage in L-arginine-induced experimental acute pancreatitis.

PubMed

Jamdar, Saurabh; Babu, Benoy I; Nirmalan, Mahesh; Jeziorska, Maria; McMahon, Raymond F T; Siriwardena, Ajith K

2013-11-10

Microvascular thrombosis is a critical event in severe acute pancreatitis. Human recombinant activated protein C (Xigris®, Eli Lilly, Indianapolis, IN, USA) modulates the interplay between pro-inflammatory and pro-coagulant pathways and maintains microvascular patency. However, the anticoagulant properties of Xigris® may precipitate bleeding from the inflamed pancreas. This study tests the hypothesis that Xigris® can ameliorate experimental acute pancreatitis without causing pancreatic haemorrhage. Sprague Dawley rats were allocated as follows: Group 1: control (n=7); Group 2: acute pancreatitis (n=6); Group 3: administration of Xigris® 500 µg/kg body weight before induction of acute pancreatitis (n=6); and Group 4: Administration of Xigris® 500 µg/kg body weight 30 minutes after induction of acute pancreatitis (n=6). Acute pancreatitis was induced by intraperitoneal administration of L-arginine 300 mg/100 g body weight. Animals were sacrificed at 48 hours and biochemical, haematological, and histological markers of pancreatic haemorrhage and inflammation assessed. Median lipase in animals with acute pancreatitis was 10 U/mL (range: 7-16 U/mL) compared to 5.5 (range: 3-8 U/mL) in controls (P=0.028). Lipase was also elevated in animals given Xigris® both before (12 U/mL, range: 8-22 U/mL; P=0.031 vs. control group) and after (46 U/mL, range: 9-71 U/mL; P=0.015 vs. control group) induction of acute pancreatitis). Haemoglobin levels were similar among all groups (P=0.323). There was no histological evidence of pancreatic haemorrhage in animals treated with Xigris®. Pre-treatment with Xigris® was associated with a significant reduction in pancreatic injury. This effect was absent when Xigris® was administered after induction of acute pancreatitis. Xigris® did not lead to pancreatic haemorrhage in experimental acute pancreatitis. Administration of Xigris® prior to induction of acute pancreatitis was associated with amelioration of injury. This effect was not seen with administration of Xigris® after induction of acute pancreatitis.

Neogene Gas Total Petroleum System -- Neogene Nonassociated Gas Assessment Unit of the San Joaquin Basin Province: Chapter 22 in Petroleum systems and geologic assessment of oil and gas in the San Joaquin Basin Province, California

USGS Publications Warehouse

Hosford Scheirer, Allegra; Magoon, Leslie B.

2009-01-01

The Neogene Nonassociated Gas Assessment Unit (AU) of the Neogene Total Petroleum System consists of nonassociated gas accumulations in Pliocene marine and brackish-water sandstone located in the south and central San Joaquin Basin Province (Rudkin, 1968). Traps consist mainly of stratigraphic lenses in low-relief, elongate domes that trend northwest-southeast. Reservoir rocks typically occur as sands that pinch out at shallow depths (1,000 to 7,500 feet) within the Etchegoin and San Joaquin Formations. Map boundaries of the assessment unit are shown in figures 22.1 and 22.2; this assessment unit replaces the Pliocene Nonassociated Gas play 1001 (shown by purple line in fig. 22.1) considered by the U.S. Geological Survey (USGS) in its 1995 National Assessment (Beyer, 1996). The AU is drawn to include all existing fields containing nonassociated gas accumulations in the Pliocene to Pleistocene section, as was done in the 1995 assessment, but it was greatly expanded to include adjacent areas believed to contain similar source and reservoir rock relationships. Stratigraphically, the AU extends from the topographic surface to the base of the Etchegoin Formation (figs. 22.3 and 22.4). The boundaries of the AU explicitly exclude gas accumulations in Neogene rocks on the severely deformed west side of the basin and gas accumulations in underlying Miocene rocks; these resources, which primarily consist of a mixture of mostly thermogenic and some biogenic gas, are included in two other assessment units. Lillis and others (this volume, chapter 10) discuss the geochemical characteristics of biogenic gas in the San Joaquin Basin Province. Primary fields in the assessment unit are defined as those containing hydrocarbon resources greater than the USGS minimum threshold for assessment—3 billion cubic feet (BCF) of gas; secondary fields contain smaller volumes of gas but constitute a significant show of hydrocarbons. Although 12 fields meet the 3 BCF criterion for inclusion in the AU, only 5 fields were considered at the time of assessment.

Effects of teriparatide and risedronate on new fractures in post-menopausal women with severe osteoporosis (VERO): a multicentre, double-blind, double-dummy, randomised controlled trial.

PubMed

Kendler, David L; Marin, Fernando; Zerbini, Cristiano A F; Russo, Luis A; Greenspan, Susan L; Zikan, Vit; Bagur, Alicia; Malouf-Sierra, Jorge; Lakatos, Péter; Fahrleitner-Pammer, Astrid; Lespessailles, Eric; Minisola, Salvatore; Body, Jean Jacques; Geusens, Piet; Möricke, Rüdiger; López-Romero, Pedro

2017-11-09

No clinical trials have compared osteoporosis drugs with incident fractures as the primary outcome. We compared the anti-fracture efficacy of teriparatide with risedronate in patients with severe osteoporosis. In this double-blind, double-dummy trial, we enrolled post-menopausal women with at least two moderate or one severe vertebral fracture and a bone mineral density T score of less than or equal to -1·50. Participants were randomly assigned to receive 20 μg of teriparatide once daily plus oral weekly placebo or 35 mg of oral risedronate once weekly plus daily injections of placebo for 24 months. The primary outcome was new radiographic vertebral fractures. Secondary, gated outcomes included new and worsened radiographic vertebral fractures, clinical fractures (a composite of non-vertebral and symptomatic vertebral), and non-vertebral fractures. This study is registered with ClinicalTrials.gov (NCT01709110) and EudraCT (2012-000123-41). We enrolled 680 patients in each group. At 24 months, new vertebral fractures occurred in 28 (5·4%) of 680 patients in the teriparatide group and 64 (12·0%) of 680 patients in the risedronate group (risk ratio 0·44, 95% CI 0·29-0·68; p<0·0001). Clinical fractures occurred in 30 (4·8%) of 680 patients in the teriparatide group compared with 61 (9·8%) of 680 in the risedronate group (hazard ratio 0·48, 95% CI 0·32-0·74; p=0·0009). Non-vertebral fragility fractures occurred in 25 (4·0%) patients in the teriparatide group and 38 (6·1%) in the risedronate group (hazard ratio 0·66; 95% CI 0·39-1·10; p=0·10). Among post-menopausal women with severe osteoporosis, the risk of new vertebral and clinical fractures is significantly lower in patients receiving teriparatide than in those receiving risedronate. Lilly. Copyright © 2017 Elsevier Ltd. All rights reserved.

Out-of-pocket drug costs and drug utilization patterns of postmenopausal Medicare beneficiaries with osteoporosis.

PubMed

Conwell, Leslie Jackson; Esposito, Dominick; Garavaglia, Susan; Meadows, Eric S; Colby, Margaret; Herrera, Vivian; Goldfarb, Seth; Ball, Daniel; Marciniak, Martin

2011-08-01

The Medicare Part D coverage gap has been associated with lower adherence and drug utilization and higher discontinuation. Because osteoporosis has a relatively high prevalence among Medicare-eligible postmenopausal women, we examined changes in utilization of osteoporosis medications during this coverage gap. The purpose of this study was to investigate changes in out-of-pocket (OOP) drug costs and utilization associated with the Medicare Part D coverage gap among postmenopausal beneficiaries with osteoporosis. This retrospective analysis of 2007 pharmacy claims focuses on postmenopausal female Medicare beneficiaries enrolled in full-, partial-, or no-gap exposure standard or Medicare Advantage prescription drug plans (PDPs), retiree drug subsidy (RDS) plans, or the low-income subsidy program. We compared beneficiaries with osteoporosis who were taking teriparatide (Eli Lilly and Company, Indianapolis, Indiana) (n = 5657) with matched samples of beneficiaries who were taking nonteriparatide osteoporosis medications (NTO; n = 16,971) or who had other chronic conditions (OCC; n = 16,971). We measured average monthly prescription drug fills and OOP costs, medication discontinuation, and skipping. More than half the sample reached the coverage gap; OOP costs then rose for teriparatide users enrolled in partial- or full-gap exposure plans (increase of 121% and 186%; $300 and $349) but fell for those in no-gap exposure PDPs or RDS plans (decrease of 49% and 30%; $131 and $40). OOP costs for beneficiaries in partial- or full-gap exposure PDPs increased >120% (increase of $144 and $176) in the NTO group and nearly doubled for the OCC group (increase of $124 and $151); these OOP costs were substantially lower than those for teriparatide users. Both teriparatide users and NTO group members discontinued or skipped medications more often than persons in the OCC group, regardless of plan or benefit design. Medication discontinuation and OOP costs among beneficiaries with osteoporosis were highest for those enrolled in Part D plans with a coverage gap. Providers should be aware of potential cost-related nonadherence among Medicare beneficiaries taking osteoporosis medications. Copyright © 2011 Elsevier HS Journals, Inc. All rights reserved.

Impact of Pretreatment With Antidepressants on the Efficacy of Duloxetine in Terms of Mood Symptoms and Functioning: An Analysis of 15 Pooled Major Depressive Disorder Studies

PubMed Central

Barros, Bruno R.; Schacht, Alexander; Happich, Michael; Televantou, Foula; Berggren, Lovisa; Walker, Daniel J.

2014-01-01

Objective: This post hoc analysis aimed to determine whether patients with major depressive disorder (MDD) in duloxetine trials who were antidepressant naive or who were previously exposed to antidepressants exhibited differences in efficacy and functioning. Method: Data were pooled from 15 double-blind, placebo- and/or active-controlled duloxetine trials of adult patients with MDD conducted by Eli Lilly and Company. The individual studies took place between March 2000 and November 2009. Data were analyzed using 4 pretreatment subgroups: first-episode never treated, multiple-episode never treated, treated previously only with selective serotonin reuptake inhibitors (SSRIs), and previously treated with antidepressants other than just SSRIs. Measures included the 17-item Hamilton Depression Rating Scale (HDRS-17) total and somatic symptom subscale scores, Montgomery-Asberg Depression Rating Scale (MADRS) total score, and Sheehan Disability Scale total score. Response rates (50% and 30%) were based on the HDRS-17 total score and remission rates on either the HDRS-17 or MADRS total score. Results: Response and remission rates were significantly greater (P < .05 in 11 of 12 comparisons) for duloxetine versus placebo in the 4 subgroups. A trend of greater response and remission occurred for first-episode versus multiple-episode patients; both groups were generally higher than the antidepressant-treated groups. Mean changes in efficacy measures were mostly significantly greater (P < .05 in 13 of 16 comparisons) for duloxetine versus placebo within each pretreatment subgroup, with some (P < .05 in 2 of 24 comparisons) significant interaction effects between subgroups on HDRS-17 total and somatic symptoms scores. Conclusions: Duloxetine was generally superior to placebo on response and remission rates and in mean change on efficacy measures. Response and remission rates were numerically greater for first-episode versus multiple-episode and drug-treated patients. Mean change differences on efficacy measures among the 4 subgroups were inconsistent. Duloxetine showed a similar therapeutic effect independent of episode frequency and antidepressant pretreatment. PMID:25667808

Effect of Mars Atmospheric Loss on Snow Melt Potential in a 3.5 Gyr Mars Climate Evolution Model

NASA Astrophysics Data System (ADS)

Mansfield, Megan; Kite, Edwin S.; Mischna, Michael A.

2018-04-01

Post-Noachian Martian paleochannels indicate the existence of liquid water on the surface of Mars after about 3.5 Gya (Irwin et al., 2015, https://doi.org/10.1016/j.geomorph.2014.10.012; Palucis et al., 2016, https://doi.org/10.1002/2015JE004905). In order to explore the effects of variations in CO2 partial pressure and obliquity on the possibility of surface water, we created a zero-dimensional surface energy balance model. We combine this model with physically consistent orbital histories to track conditions over the last 3.5 Gyr of Martian history. We find that melting is allowed for atmospheric pressures corresponding to exponential loss rates of dP/dt∝t-3.73 or faster, but this rate is within 0.5σ of the rate calculated from initial measurements made by the Mars Atmosphere and Volatile EvolutioN (MAVEN) mission, if we assume all the escaping oxygen measured by MAVEN comes from atmospheric CO2 (Lillis et al., 2017, https://doi.org/10.1002/2016JA023525; Tu et al., 2015, https://doi.org/10.1051/0004-6361/201526146). Melting at this loss rate matches selected key geologic constraints on the formation of Hesperian river networks, assuming optimal melt conditions during the warmest part of each Mars year (Irwin et al., 2015, https://doi.org/10.1016/j.geomorph.2014.10.012; Kite, Gao, et al., 2017, https://doi.org/10.1038/ngeo3033; Kite, Sneed et al., 2017, https://doi.org/10.1002/2017GL072660; Stopar et al., 2006, https://doi.org/10.1016/j.gca.2006.07.039). The atmospheric pressure has a larger effect on the surface energy than changes in Mars's mean obliquity. These results show that initial measurements of atmosphere loss by MAVEN are consistent with atmospheric loss being the dominant process that switched Mars from a melt-permitting to a melt-absent climate (Jakosky et al., 2017, https://doi.org/10.1126/science.aai7721), but non-CO2 warming will be required if <2 Gya paleochannels are confirmed or if most of the escaping oxygen measured by MAVEN comes from H2O.

Characteristics, Treatment Patterns, and Economic Outcomes of Patients Initiating Injectable Medications for Management of Type 2 Diabetes Mellitus in Japan: Results from a Retrospective Claims Database Analysis.

PubMed

Suzuki, Shuichi; Desai, Urvi; Strizek, Alena; Ivanova, Jasmina; Garcia-Horton, Viviana; Cai, Zhihong; Schmerold, Luke; Liu, Xinyue; Perez-Nieves, Magaly

2018-06-01

This study's objective was to describe characteristics, treatment patterns, and economic outcomes of type 2 diabetes mellitus (T2DM) patients initiating injectable antidiabetic medications in Japan. Adults (≥ 18 years) with T2DM, ≥ 2 claims for injectable antidiabetics between 1 August 2011 and 31 July 2015 (first claim = index date), no evidence of type 1 diabetes mellitus, ≤ 1 claim for insulin, no claims for GLP-1RA before index, and continuous enrollment for 6 months before (baseline) and 12 months after index (follow-up) were selected from the Japan Medical Center Database. Patient characteristics and outcomes during the baseline and follow-up periods were described overall and by provider, using the proxy setting of index medication [hospital (including outpatient departments) for specialists; clinic for general practitioner (GP)]. Of the 2683 patients included (mean age: 50 years, 67% male), 1879 (70%) initiated injectable antidiabetics with specialists and 804 (30%) with GPs. The specialist cohort had a significantly greater comorbidity burden, but lower HbA1c levels during baseline, and was more likely to receive intensified treatment at index than the GP cohort. Almost 40% of patients (almost 30% of GP cohort) did not use antidiabetics during baseline; the remaining patients received oral medications, primarily from GPs. During follow-up, patients used the index medication for approximately 7 months. Independent of specialist vs. GP setting, patients received antidiabetics and medications for T2DM-related comorbidities and complications during the baseline and follow-up periods from the same provider, primarily GPs. The overall average healthcare costs were ¥350,404 during baseline and ¥1,856,727 during follow-up. In Japan, most T2DM patients initiated injectable antidiabetics with specialists vs. GPs. There were considerable differences in characteristics of patients treated by specialists vs. GPs. After initiation, injectable antidiabetics were largely prescribed by GPs. Future research should evaluate the factors associated with different provider practices and communication channels between specialists and GPs to improve patient management. Eli Lilly and Co.

Hypoglycemia and diabetes: a report of a workgroup of the American Diabetes Association and the Endocrine Society.

PubMed

Seaquist, Elizabeth R; Anderson, John; Childs, Belinda; Cryer, Philip; Dagogo-Jack, Samuel; Fish, Lisa; Heller, Simon R; Rodriguez, Henry; Rosenzweig, James; Vigersky, Robert

2013-05-01

To review the evidence about the impact of hypoglycemia on patients with diabetes that has become available since the past reviews of this subject by the American Diabetes Association and The Endocrine Society and to provide guidance about how this new information should be incorporated into clinical practice. Five members of the American Diabetes Association and five members of The Endocrine Society with expertise in different aspects of hypoglycemia were invited by the Chair, who is a member of both, to participate in a planning conference call and a 2-day meeting that was also attended by staff from both organizations. Subsequent communications took place via e-mail and phone calls. The writing group consisted of those invitees who participated in the writing of the manuscript. The workgroup meeting was supported by educational grants to the American Diabetes Association from Lilly USA, LLC and Novo Nordisk and sponsorship to the American Diabetes Association from Sanofi. The sponsors had no input into the development of or content of the report. The writing group considered data from recent clinical trials and other studies to update the prior workgroup report. Unpublished data were not used. Expert opinion was used to develop some conclusions. Consensus was achieved by group discussion during conference calls and face-to-face meetings, as well as by iterative revisions of the written document. The document was reviewed and approved by the American Diabetes Association's Professional Practice Committee in October 2012 and approved by the Executive Committee of the Board of Directors in November 2012 and was reviewed and approved by The Endocrine Society's Clinical Affairs Core Committee in October 2012 and by Council in November 2012. The workgroup reconfirmed the previous definitions of hypoglycemia in diabetes, reviewed the implications of hypoglycemia on both short- and long-term outcomes, considered the implications of hypoglycemia on treatment outcomes, presented strategies to prevent hypoglycemia, and identified knowledge gaps that should be addressed by future research. In addition, tools for patients to report hypoglycemia at each visit and for clinicians to document counseling are provided.

Efficacy and safety of AIR inhaled insulin compared to insulin lispro in patients with type 1 diabetes mellitus in a 6-month, randomized, noninferiority trial.

PubMed

Comulada, Angel L; Renard, Eric; Nakano, Masako; Rais, Nadeem; Mao, Xuejing; Webb, David M; Milicevic, Zvonko

2009-09-01

Patients with type 1 diabetes may prefer features of AIR inhaled insulin (developed by Alkermes, Inc. [Cambridge, MA] and Eli Lilly and Company [Indianapolis, IN]; AIR is a registered trademark of Alkermes, Inc.) over insulin injection, but the two methods need to be compared for efficacy and safety. This multicenter, 6-month, parallel-group, noninferiority trial had 500 patients with type 1 diabetes randomized to morning doses of basal insulin glargine plus either preprandial injectable insulin lispro or preprandial AIR insulin. We hypothesized that AIR insulin is noninferior (upper bound of the 95% confidence interval < or = 0.4%) to insulin lispro for change-from-baseline hemoglobin A1C (A1C). Baseline A1C was 7.95 +/- 0.08% for both groups. At end point, A1C was lower with insulin lispro than with AIR insulin by 0.27% (95% confidence interval 0.11, 0.43; P< 0.001). Noninferiority of AIR insulin to insulin lispro was not demonstrated, but similar percentages of patients in each group achieved A1C <7.0% (P = 0.448). Overall daily blood glucose was similar between groups at baseline (P = 0.879) and end point (P = 0.161). Two-hour postprandial blood glucose change from baseline was significantly (P < 0.001) higher with AIR insulin (20.77 +/- 4.33 mg/dL at 3 months and 15.85 +/- 3.08 mg/dL at end point) than with insulin lispro (3.29 +/- 4.14 mg/dL at 3 months and 1.67 +/- 2.91 mg/dL at end point). Overall hypoglycemia was similar between treatment groups (P = 0.355). The AIR insulin group had greater decrease in diffusing capacity of the lung for carbon monoxide at end point (P = 0.020) and greater incidence of cough (P = 0.024) and dyspnea (P = 0.030). Body weight decreased in the AIR insulin group and increased in the insulin lispro group. Insulin lispro provided lower A1C than AIR insulin, but the difference may not be clinically relevant.

Hypoglycemia and Diabetes: A Report of a Workgroup of the American Diabetes Association and The Endocrine Society

PubMed Central

Anderson, John; Childs, Belinda; Cryer, Philip; Dagogo-Jack, Samuel; Fish, Lisa; Heller, Simon R.; Rodriguez, Henry; Rosenzweig, James; Vigersky, Robert

2013-01-01

OBJECTIVE To review the evidence about the impact of hypoglycemia on patients with diabetes that has become available since the past reviews of this subject by the American Diabetes Association and The Endocrine Society and to provide guidance about how this new information should be incorporated into clinical practice. PARTICIPANTS Five members of the American Diabetes Association and five members of The Endocrine Society with expertise in different aspects of hypoglycemia were invited by the Chair, who is a member of both, to participate in a planning conference call and a 2-day meeting that was also attended by staff from both organizations. Subsequent communications took place via e-mail and phone calls. The writing group consisted of those invitees who participated in the writing of the manuscript. The workgroup meeting was supported by educational grants to the American Diabetes Association from Lilly USA, LLC and Novo Nordisk and sponsorship to the American Diabetes Association from Sanofi. The sponsors had no input into the development of or content of the report. EVIDENCE The writing group considered data from recent clinical trials and other studies to update the prior workgroup report. Unpublished data were not used. Expert opinion was used to develop some conclusions. CONSENSUS PROCESS Consensus was achieved by group discussion during conference calls and face-to-face meetings, as well as by iterative revisions of the written document. The document was reviewed and approved by the American Diabetes Association’s Professional Practice Committee in October 2012 and approved by the Executive Committee of the Board of Directors in November 2012 and was reviewed and approved by The Endocrine Society’s Clinical Affairs Core Committee in October 2012 and by Council in November 2012. CONCLUSIONS The workgroup reconfirmed the previous definitions of hypoglycemia in diabetes, reviewed the implications of hypoglycemia on both short- and long-term outcomes, considered the implications of hypoglycemia on treatment outcomes, presented strategies to prevent hypoglycemia, and identified knowledge gaps that should be addressed by future research. In addition, tools for patients to report hypoglycemia at each visit and for clinicians to document counseling are provided. PMID:23589542

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes.

PubMed

Wanner, Christoph; Inzucchi, Silvio E; Lachin, John M; Fitchett, David; von Eynatten, Maximilian; Mattheus, Michaela; Johansen, Odd Erik; Woerle, Hans J; Broedl, Uli C; Zinman, Bernard

2016-07-28

Diabetes confers an increased risk of adverse cardiovascular and renal events. In the EMPA-REG OUTCOME trial, empagliflozin, a sodium-glucose cotransporter 2 inhibitor, reduced the risk of major adverse cardiovascular events in patients with type 2 diabetes at high risk for cardiovascular events. We wanted to determine the long-term renal effects of empagliflozin, an analysis that was a prespecified component of the secondary microvascular outcome of that trial. We randomly assigned patients with type 2 diabetes and an estimated glomerular filtration rate of at least 30 ml per minute per 1.73 m(2) of body-surface area to receive either empagliflozin (at a dose of 10 mg or 25 mg) or placebo once daily. Prespecified renal outcomes included incident or worsening nephropathy (progression to macroalbuminuria, doubling of the serum creatinine level, initiation of renal-replacement therapy, or death from renal disease) and incident albuminuria. Incident or worsening nephropathy occurred in 525 of 4124 patients (12.7%) in the empagliflozin group and in 388 of 2061 (18.8%) in the placebo group (hazard ratio in the empagliflozin group, 0.61; 95% confidence interval, 0.53 to 0.70; P<0.001). Doubling of the serum creatinine level occurred in 70 of 4645 patients (1.5%) in the empagliflozin group and in 60 of 2323 (2.6%) in the placebo group, a significant relative risk reduction of 44%. Renal-replacement therapy was initiated in 13 of 4687 patients (0.3%) in the empagliflozin group and in 14 of 2333 patients (0.6%) in the placebo group, representing a 55% lower relative risk in the empagliflozin group. There was no significant between-group difference in the rate of incident albuminuria. The adverse-event profile of empagliflozin in patients with impaired kidney function at baseline was similar to that reported in the overall trial population. In patients with type 2 diabetes at high cardiovascular risk, empagliflozin was associated with slower progression of kidney disease and lower rates of clinically relevant renal events than was placebo when added to standard care. (Funded by the Boehringer Ingelheim and Eli Lilly and Company Diabetes Alliance; EMPA-REG OUTCOME ClinicalTrials.gov number, NCT01131676.).

Using GRIDVIEW to Better Understand the Early Bombardment History of the Moon, Mars and Earth

NASA Technical Reports Server (NTRS)

Frey, Herbert

2012-01-01

For more than a decade we have used GRIDVIEW to help analyze topographic and related data for Mars and more recently for the Moon. Our focus has been to employ the stretching, contouring, profiling, circle-fitting and other capabilities of GRIDVIEW to search for Quasi-Circular Depressions (CTAs) in MOLA, LOLA and other topographic data, and for Circular Thin Areas (CTAs) in Mars and Moon model crustal thickness data. Both QCDs and CTAs likely represent buried or obscured impact craters not readily visible in image data. We found clear evidence for a much larger population of buried impact craters in the northern lowlands of Mars (Frey et al. 2002), suggesting that part of the Red Planet is not significantly younger than the southern highlands. Edgar and Frey (2008) found that the N(300) crater retention ages of both areas were essentially identical, a conclusion confirmed by Wyatt (unpublished data) using more recent crustal thickness data for Mars. MOLA topographic data and MOLA-derived crustal thickness data were used to both identify a large number of previously unrecognized very large impact basins (D> 1000 km) on Mars and to determine relative crater retention ages for them (Frey, 2008). The distribution of N(300) CRAs suggested most formed in a relatively short interval of time. This dating also suggested the main magnetic field of Mars disappeared during this period (Lillis et al., 2008), because only the youngest basins systematically lack a remagnetized signature. Similar QCD and CTA analysis of first Clementine (Frey, 2011) and more recently LOLA topographic and LOLA-derived crustal thickness data for the Moon (Frey et al., 2011) revealed a significantly larger population of impact basins > 300 km in diameter than previously known. N(50) CRAs suggest a two-peak distribution of ages (Frey, 2012). An improved counting process confirms the two peaks, perhaps indicating both a pre-Nectaris Early Heavy Bombardment (EHB) as well as a Late Heavy Bombardment (LHB) on the Moon (Frey and Burgess, 2012, this meeting), with obvious implications for the early bombardment history of the Earth.

Treatment patterns in patients with type 2 diabetes mellitus treated with glucagon-like peptide-1 receptor agonists: Higher adherence and persistence with dulaglutide compared with once-weekly exenatide and liraglutide.

PubMed

Alatorre, Carlos; Fernández Landó, Laura; Yu, Maria; Brown, Katelyn; Montejano, Leslie; Juneau, Paul; Mody, Reema; Swindle, Ralph

2017-07-01

To compare adherence (proportion of days covered [PDC]), persistence, and treatment patterns among patients with type 2 diabetes mellitus (T2DM) newly initiating glucagon-like peptide-1 receptor agonists (GLP-1RAs). More specifically, the main objectives were to compare dulaglutide vs exenatide once weekly and dulaglutide vs liraglutide. Patients with T2DM newly initiating dulaglutide, albiglutide, exenatide once weekly, exenatide twice daily and liraglutide between November 2014 and April 2015 were hierarchically selected from Truven Health's MarketScan Research Databases. Propensity score matching was used to account for selection bias. Adherence to and persistence with the index GLP-1RA, and switching and augmentation patterns were assessed during the 6-month post-index period. Mean adherence for the matched cohorts was significantly higher for dulaglutide than for exenatide once weekly (0.72 vs 0.61; P  < .0001) and liraglutide (0.71 vs 0.67; P  < .0001). The percentage of patients achieving PDC ≥ 0.80 was significantly higher for dulaglutide compared with exenatide once weekly (54.2% vs 37.9%; P  < .0001) and liraglutide (53.5% vs 44.3%; P  < .0001). The mean (standard deviation) days on treatment for all matched patients was significantly higher for patients in the dulaglutide cohort compared with those in the exenatide once-weekly (148.4 [55.4] vs 123.6 [61.6]; P  < .0001) and liraglutide cohorts (146.0 [56.9] vs 137.4 [60.1]; P  < .0001). A significantly lower proportion of patients on dulaglutide discontinued treatment compared with those on exenatide once weekly (26.2% vs 48.4%; P  < .0001) and those on liraglutide (28.0% vs 35.6%; P  < .0001). Dulaglutide initiators had significantly higher adherence, were more persistent, and had lower discontinuation rates compared with initiators of exenatide once weekly or liraglutide during the 6-month follow-up period. © 2017 Eli Lilly and Company. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.

Cost-effectiveness of pemetrexed in combination with cisplatin as first line treatment for patients with advanced non-squamous non-small-cell lung cancer in Spain.

PubMed

González García, Jonathan; Gutiérrez Nicolás, Fernando; Nazco Casariego, Gloria Julia; Valcárcel Nazco, Cristina; Batista López, Jose Norberto; Oramas Rodríguez, Juana

2017-01-01

Lung cancer is the third most frequent neoplastic tumour in Spain, with around 27 000 new cases diagnosed per year; 80-95% of these are non-small-cell cancer (NSCLC), and the majority of cases are diagnosed in advanced stages of the disease, and for this reason it is one of the oncologic conditions with higher mortality rates (21.4% mean survival at 5 years). The main treatment regimens used for first-line treatment of NSCLC are: cisplatin/pemetrexed (cis/pem), cisplatin/gemcitabine/ bevacizumab (cis/gem/bev), and carboplatin/paclitaxel/ bevacizumab (carb/pac/bev). The objective of this study was to evaluate the cost-effectiveness ratio of antineoplastic 1st line NSCLC treatment regimens, from the point of view of hospital management. A cost-efficacy mathematical model was prepared, based on a decision tree. The efficacy variable was Progression Free Survival, obtained from the PARAMOUNT, AVAIL and SAIL Phase III clinical trials. The study was conducted from the perspective of the hospital management, considering only the direct costs of drug acquisition. A deterministic sensitivity analysis was conducted to confirm the robustness of outcomes. The PFS obtained in clinical trials with cis/pem, cis/ gem/bev and carb/pac/bev was: 6.9, 6.7 and 6.2 months, respectively. Based on our model, the mean cost of treatment per patient for these regimens was: 19 942 €, 15 594 € and 36 095 €, respectively. The incremental cost-effectiveness ratio per month of additional PFS between cis/pem and cis/gem/bev was 19 303 €. Estimating a 30% reduction in acquisition costs for pemetrexed (Alimta®Eli Lilly Nederland B.V.), due to the forthcoming launch of generic medications, the cis/pem treatment would become the predominant alternative for 1st line treatment of NSCLC patients, by offering the best health results at a lower cost. Copyright AULA MEDICA EDICIONES 2014. Published by AULA MEDICA. All rights reserved.

The mass-metallicity and fundamental metallicity relations at z > 2 using very large telescope and Subaru near-infrared spectroscopy of zCOSMOS galaxies

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

Maier, C.; Ziegler, B. L.; Lilly, S. J.

2014-09-01

In the local universe, there is good evidence that, at a given stellar mass M, the gas-phase metallicity Z is anti-correlated with the star formation rate (SFR) of the galaxies. It has also been claimed that the resulting Z(M, SFR) relation is invariant with redshift—the so-called 'fundamental metallicity relation' (FMR). Given a number of difficulties in determining metallicities, especially at higher redshifts, the form of the Z(M, SFR) relation and whether it is really independent of redshift is still very controversial. To explore this issue at z > 2, we used VLT-SINFONI and Subaru-MOIRCS near-infrared spectroscopy of 20 zCOSMOS-deep galaxiesmore » at 2.1 < z < 2.5 to measure the strengths of up to five emission lines: [O II] λ3727, Hβ, [O III] λ5007, Hα, and [N II] λ6584. This near-infrared spectroscopy enables us to derive O/H metallicities, and also SFRs from extinction corrected Hα measurements. We find that the mass-metallicity relation (MZR) of these star-forming galaxies at z ≈ 2.3 is lower than the local Sloan Digital Sky Survey (SDSS) MZR by a factor of three to five, a larger change than found by Erb et al. using [N II]/Hα-based metallicities from stacked spectra. We discuss how the different selections of the samples and metallicity calibrations used may be responsible for this discrepancy. The galaxies show direct evidence that the SFR is still a second parameter in the MZR at these redshifts. However, determining whether the Z(M, SFR) relation is invariant with epoch depends on the choice of extrapolation used from local samples, because z > 2 galaxies of a given mass have much higher SFRs than the local SDSS galaxies. We find that the zCOSMOS galaxies are consistent with a non-evolving FMR if we use the physically motivated formulation of the Z(M, SFR) relation from Lilly et al., but not if we use the empirical formulation of Mannucci et al.« less

Modeling of Marine Natural Hazards in the Lesser Antilles

NASA Astrophysics Data System (ADS)

Zahibo, Narcisse; Nikolkina, Irina; Pelinovsky, Efim

2010-05-01

The Caribbean Sea countries are often affected by various marine natural hazards: hurricanes and cyclones, tsunamis and flooding. The historical data of marine natural hazards for the Lesser Antilles and specially, for Guadeloupe are presented briefly. Numerical simulation of several historical tsunamis in the Caribbean Sea (1755 Lisbon trans-Atlantic tsunami, 1867 Virgin Island earthquake tsunami, 2003 Montserrat volcano tsunami) are performed within the framework of the nonlinear-shallow theory. Numerical results demonstrate the importance of the real bathymetry variability with respect to the direction of propagation of tsunami wave and its characteristics. The prognostic tsunami wave height distribution along the Caribbean Coast is computed using various forms of seismic and hydrodynamics sources. These results are used to estimate the far-field potential for tsunami hazards at coastal locations in the Caribbean Sea. The nonlinear shallow-water theory is also applied to model storm surges induced by tropical cyclones, in particular, cyclones "Lilli" in 2002 and "Dean" in 2007. Obtained results are compared with observed data. The numerical models have been tested against known analytical solutions of the nonlinear shallow-water wave equations. Obtained results are described in details in [1-7]. References [1] N. Zahibo and E. Pelinovsky, Natural Hazards and Earth System Sciences, 1, 221 (2001). [2] N. Zahibo, E. Pelinovsky, A. Yalciner, A. Kurkin, A. Koselkov and A. Zaitsev, Oceanologica Acta, 26, 609 (2003). [3] N. Zahibo, E. Pelinovsky, A. Kurkin and A. Kozelkov, Science Tsunami Hazards. 21, 202 (2003). [4] E. Pelinovsky, N. Zahibo, P. Dunkley, M. Edmonds, R. Herd, T. Talipova, A. Kozelkov and I. Nikolkina, Science of Tsunami Hazards, 22, 44 (2004). [5] N. Zahibo, E. Pelinovsky, E. Okal, A. Yalciner, C. Kharif, T. Talipova and A. Kozelkov, Science of Tsunami Hazards, 23, 25 (2005). [6] N. Zahibo, E. Pelinovsky, T. Talipova, A. Rabinovich, A. Kurkin and I. Nikolkina, Atmospheric Research. 84, 13 (2007). [7] Zahibo, N., Pelinovsky, E., Kurkin, A., and Nikolkina, I. Tsunami hazard for the French West Indies, Lesser Antilles. Integrated Coastal Zone Management (Ed. R. KRISHNAMURTHY). Re-search Publ., Singapore, 2008, 517-535.

SU-E-J-134: Optimizing Technical Parameters for Using Atlas Based Automatic Segmentation for Evaluation of Contour Accuracy Experience with Cardiac Structures From NRG Oncology/RTOG 0617

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

Yu, J; Gong, Y; Bar-Ad, V

Purpose: Accurate contour delineation is crucial for radiotherapy. Atlas based automatic segmentation tools can be used to increase the efficiency of contour accuracy evaluation. This study aims to optimize technical parameters utilized in the tool by exploring the impact of library size and atlas number on the accuracy of cardiac contour evaluation. Methods: Patient CT DICOMs from RTOG 0617 were used for this study. Five experienced physicians delineated the cardiac structures including pericardium, atria and ventricles following an atlas guideline. The consistency of cardiac structured delineation using the atlas guideline was verified by a study with four observers and seventeenmore » patients. The CT and cardiac structure DICOM files were then used for the ABAS technique.To study the impact of library size (LS) and atlas number (AN) on automatic contour accuracy, automatic contours were generated with varied technique parameters for five randomly selected patients. Three LS (20, 60, and 100) were studied using commercially available software. The AN was four, recommended by the manufacturer. Using the manual contour as the gold standard, Dice Similarity Coefficient (DSC) was calculated between the manual and automatic contours. Five-patient averaged DSCs were calculated for comparison for each cardiac structure.In order to study the impact of AN, the LS was set 100, and AN was tested from one to five. The five-patient averaged DSCs were also calculated for each cardiac structure. Results: DSC values are highest when LS is 100 and AN is four. The DSC is 0.90±0.02 for pericardium, 0.75±0.06 for atria, and 0.86±0.02 for ventricles. Conclusion: By comparing DSC values, the combination AN=4 and LS=100 gives the best performance. This project was supported by NCI grants U24CA12014, U24CA180803, U10CA180868, U10CA180822, PA CURE grant and Bristol-Myers Squibb and Eli Lilly.« less

Evaluation of Plant- Compost -Microorganisms Synergy for the Remediation of Diesel contaminated Soil: Success Stories from the Field Station

NASA Astrophysics Data System (ADS)

Hussain, Imran; Wimmer, Bernhard; Soja, Gerhard; Sessitsch, Angela; Reichenauer, Thomas G.

2016-04-01

Total petroleum hydrocarbons (TPH) contain a mixture of crude oil, gasoline, creosote and diesel is one of the most common groups of persistent organic pollutants. TPH enters into the ecosystem (soil, water and air) through leakage of underground storage tanks (LUST), accidental oil spills, transportation losses and industrial processes. Pollution associated with diesel oil and its refined products is of great concern worldwide due to its threats/damages for human and ecosystem health, soil structure and ground water quality. Extensive soils pollution with petroleum hydrocarbons results in extreme harsh surroundings, produce hydrophobic conditions and infertile soils that ultimately lead towards less plant and microorganisms growth. Among biological methods, bioremediation and phytoremediation are promising technologies that have both technical and ecological benefits as compared to convention methods. Within phytoremediation, rhizoremediation based on stimulation of degrading microorganism's population influenced by plant rhizospheric effect is known as main mechanism for phytoremediation of petroleum polluted soils. Composting along with rhizodegradtion was used to remediate freshly spilled soils at Lysimeter station Siebersdof, Austria. Experiment was started in July 2013 and will be monitored up to September 2016. Field station has 12 Lysimeter in total; each has length, width and depth of 100 cm respectively. Each Lysimeter was filled with normal agricultural soil from Siebersdof (0-70 cm), sand (70-85 cm) and stones (85-100cm). Sand and stones were added to support the normal leaching and percolation of water as we collected leachate samples after regular intervals. After filling, commercial diesel oil (2% w/w of 0-70 cm soil) was spilled on top of each Lysimeter as accidental spill occurs in filed. Compost was added at 0-15 cm layer (5% w/w of soil) to stimulate plant as well as microorganisms growth. Whole Lysimeter station was divided into three treatments and four replicates; T1 was only planted with Lolium multiflorum and Lotus corniculatus, T2 was planted with both above mentioned plants inoculated with microbial consortium (mixture of strains: Pantoea sp. strains, ITSI10, BTRH79 and Pseudomonas sp. strain, MixRI75)and T3 was kept unplanted to support bioremediation. Germination percentage (GP) was monitored weekly until three weeks after seed sowing. Biometric parameters (plant height, fresh and dry weight of shoots) and leaf chlorophyll content were recorded in periodic intervals. Soil samples were taken in regular intervals (after every 6 month) and PHC content was measured by GC-FID. In the presentation we will report about the development of plants and the degradation of petroleum hydrocarbons in Lysimeter. The degradation of TPH will be reported for 7 layers inside each Lysimeter as well as in leachate samples.

E-960

NASA Image and Video Library

1953-04-27

In the center foreground of this 1953 hanger photo is the YF-84A (NACA 134/Air Force 45-59490) used for vortex generator research. It arrived on November 28, 1949, and departed on April 21, 1954. Beside it is the third D-558-1 aircraft (NACA 142/Navy 37972). This aircraft was used for a total of 78 transonic research flights from April 1949 to June 1954. It replaced the second D-558-1, lost in the crash which killed Howard Lilly. Just visible on the left edge is the nose of the first D-558-2 (NACA 143/Navy 37973). Douglas turned the aircraft over to NACA on August 31, 1951, after the contractor had completed its initial test flights. NACA only made a single flight with the aircraft, on September 17, 1956, before the program was cancelled. In the center of the photo is the B-47A (NACA 150/Air Force 49-1900). The B-47 jet bomber, with its thin, swept-back wings, and six podded engines, represented the state of the art in aircraft design in the early 1950s. The aircraft undertook a number of research activities between May 1953 and its 78th and final research flight on November 22, 1957. The tests showed that the aircraft had a buffeting problem at speeds above Mach 0.8. Among the pilots who flew the B-47 were later X-15 pilots Joe Walker, A. Scott Crossfield, John B. McKay, and Neil A. Armstrong. On the right side of the B-47 is NACA's X-1 (Air Force 46-063). The second XS-1 aircraft built, it was fitted with a thicker wing than that on the first aircraft, which had exceeded Mach 1 on October 14, 1947. Flight research by NACA pilots indicated that this thicker wing produced 30 percent more drag at transonic speeds compared to the thinner wing on the first X-1. After a final flight on October 23, 1951, the aircraft was grounded due to the possibility of fatigue failure of the nitrogen spheres used to pressurize the fuel tanks. At the time of this photo, in 1953, the aircraft was in storage. In 1955, the aircraft was extensively modified, becoming the X-1E. In front o

A novel derivative of doxorubicin, AD198, inhibits canine transitional cell carcinoma and osteosarcoma cells in vitro

PubMed Central

Rathore, Kusum; Cekanova, Maria

2015-01-01

Doxorubicin (DOX) is one of the most commonly used chemotherapeutic treatments for a wide range of cancers. N-benzyladriamycin-14-valerate (AD198) is a lipophilic anthracycline that has been shown to target conventional and novel isoforms of protein kinase C (PKC) in cytoplasm of cells. Because of the adverse effects of DOX, including hair loss, nausea, vomiting, liver dysfunction, and cardiotoxicity, novel derivatives of DOX have been synthesized and validated. In this study, we evaluated the effects of DOX and its derivative, AD198, on cell viability of three canine transitional cell carcinoma (K9TCC) (K9TCC#1-Lillie, K9TCC#2-Dakota, K9TCC#4-Molly) and three canine osteosarcoma (K9OSA) (K9OSA#1-Zoe, K9OSA#2-Nashville, K9OSA#3-JJ) primary cancer cell lines. DOX and AD198 significantly inhibited cell proliferation in all tested K9TCC and K9OSA cell lines in a dose-dependent manner. AD198 inhibited cell viability of tested K9TCC and K9OSA cell lines more efficiently as compared to DOX at the same concentration using MTS (3-(4,5-dimethyl-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2h-tetrazolium) assay. AD198 had lower IC50 values as compared to DOX for all tested K9TCC and K9OSA cell lines. In addition, AD198 increased apoptosis in all tested K9TCC and K9OSA cell lines. AD198 increased the caspase activity in tested K9TCC and K9OSA cell lines, which was confirmed by caspase-3/7 assay, and cleavage of poly (ADP-ribose) polymerase (PARP) was confirmed by Western blotting analysis. In addition, AD198 cleaved PKC-δ, which subsequently activated the p38 signaling pathway, resulting in the apoptosis of tested K9TCC and K9OSA cell lines. Inhibition of the p38 signaling pathway by SB203580 rescued DOX- and AD198-induced apoptosis in tested K9TCC and K9OSA cell lines. Our in vitro results suggest that AD198 might be considered as a new treatment option for K9TCC and K9OSA cell lines cancers in vivo. PMID:26451087

Evidence for Weak Crustal Magnetic Fields over the Hellas, Chryse, and Acidalia Planitiae

NASA Astrophysics Data System (ADS)

Lee, C. O.; Mitchell, D. L.; Lillis, R.; Lin, R. P.; Reme, H.; Cloutier, P. A.; Acuna, M. H.

2003-04-01

The Electron Reflectometer (ER) onboard Mars Global Surveyor (MGS) detected a plasma boundary between the ionosphere and the solar wind as the latter is diverted around and past the planet [Mitchell et al., GRL, 27, 1871, 2000; Mitchell et al., JGR, 106, 23419, 2001]. Above this boundary the 10-1000 eV electron population is dominated by solar wind electrons, while below the boundary it is dominated by ionospheric photoelectrons. This "photoelectron boundary", or PEB, is sensitive to pressure variations and moves vertically in response to changes in the ionospheric pressure from below and the solar wind pressure from above. The PEB is also sensitive to crustal magnetic fields, which locally increase the total ionospheric pressure and positively bias the PEB altitude. We have empirically modeled and removed systematic variations in the PEB altitude associated with the solar wind interaction, thus isolating perturbations caused by crustal magnetic fields. A map of the PEB altitude perturbations closely resembles maps of the horizontal component of the crustal magnetic field measured at 400 km by the MGS Magnetometer (MAG). We find a PEB altitude bias over the Hellas basin that is consistent with a horizontal magnetic field with an intensity of several nanotesla at 400 km altitude. This is compatible with upper limits to the horizontal crustal field strength set by MGS MAG measurements. Since there is no evidence for significant crustal magnetic sources within the basin from MAG data obtained during aerobraking [Acuna et al. Science, 284, 790, 1999] or from electron reflection data obtained in the mapping orbit [Lillis et al., this conference], the most likely explanation is that the observed horizontal field originates from sources around the Hellas perimeter. No detectable PEB or magnetic signature is observed over the younger Argyre and Isidis Basins. There is also evidence for a significant enhancement (several nanoteslas) in the crustal field strength over Chryse Planitia and much of Acidalia Planitia, which are thought to contain hundreds of meters of material from the main outflow channels on Mars [Carr, Lunar Planetary Sci., 18, 155, 1987]. These fields appear to extend northward from a group of crustal magnetic sources along the dichotomy boundary that were mapped by the MGS Magnetometer.

Phylogenetic reconstruction in the Order Nymphaeales: ITS2 secondary structure analysis and in silico testing of maturase k (matK) as a potential marker for DNA bar coding

PubMed Central

2012-01-01

Background The Nymphaeales (waterlilly and relatives) lineage has diverged as the second branch of basal angiosperms and comprises of two families: Cabombaceae and Nymphaceae. The classification of Nymphaeales and phylogeny within the flowering plants are quite intriguing as several systems (Thorne system, Dahlgren system, Cronquist system, Takhtajan system and APG III system (Angiosperm Phylogeny Group III system) have attempted to redefine the Nymphaeales taxonomy. There have been also fossil records consisting especially of seeds, pollen, stems, leaves and flowers as early as the lower Cretaceous. Here we present an in silico study of the order Nymphaeales taking maturaseK (matK) and internal transcribed spacer (ITS2) as biomarkers for phylogeny reconstruction (using character-based methods and Bayesian approach) and identification of motifs for DNA barcoding. Results The Maximum Likelihood (ML) and Bayesian approach yielded congruent fully resolved and well-supported trees using a concatenated (ITS2+ matK) supermatrix aligned dataset. The taxon sampling corroborates the monophyly of Cabombaceae. Nuphar emerges as a monophyletic clade in the family Nymphaeaceae while there are slight discrepancies in the monophyletic nature of the genera Nymphaea owing to Victoria-Euryale and Ondinea grouping in the same node of Nymphaeaceae. ITS2 secondary structures alignment corroborate the primary sequence analysis. Hydatellaceae emerged as a sister clade to Nymphaeaceae and had a basal lineage amongst the water lilly clades. Species from Cycas and Ginkgo were taken as outgroups and were rooted in the overall tree topology from various methods. Conclusions MatK genes are fast evolving highly variant regions of plant chloroplast DNA that can serve as potential biomarkers for DNA barcoding and also in generating primers for angiosperms with identification of unique motif regions. We have reported unique genus specific motif regions in the Order Nymphaeles from matK dataset which can be further validated for barcoding and designing of PCR primers. Our analysis using a novel approach of sequence-structure alignment and phylogenetic reconstruction using molecular morphometrics congrue with the current placement of Hydatellaceae within the early-divergent angiosperm order Nymphaeales. The results underscore the fact that more diverse genera, if not fully resolved to be monophyletic, should be represented by all major lineages. PMID:23282079

AMCP Partnership Forum: Driving Value and Outcomes in Oncology.

PubMed

2017-05-01

Innovation in cancer treatment has provided a wealth of recently available therapeutic agents and a healthy drug pipeline that promises to change the way we approach this disease and the lives of those affected in the years to come. However, the majority of these new agents, many of which are targeted to specific genomic features of various tumors, may challenge the health care system's ability to afford cancer care. This innovation drives the need to focus on the value of the treatments provided to patients with cancer and on methods to optimize the efficiency of the dollars we spend, in addition to the clinical value itself. The Academy of Managed Care Pharmacy (AMCP) convened a Partnership Forum to address how to improve value and outcomes in cancer care. In this multistakeholder forum, several areas were addressed: current methods for assessing the value of oncology products, the need for balancing population management with precision medicine, and the outlook for value-based contracting for oncology medications in managed care settings. Participants recommended ways in which stakeholders can work toward solutions in these areas. The forum brought together stakeholders from health plans, integrated delivery systems, pharmacy benefit managers, clinical practice, biopharmaceutical industry, and laboratory companies. Also participating were representatives from trade and professional associations. During this 1.5-day forum, participants identified current challenges, readiness, and ways to address value and improve outcomes in cancer therapy. Some of the challenges identified include choosing a viable (and practical) outcome target for value-based contracting in oncology, the development and use of value frameworks and clinical pathways, managing cancer diagnostics, utilization of alternative payment systems, moving from a large evidence base to a small clinical trial base in considering targeted treatments, and lack of best practices in value-based payment arrangements. Addressing these challenges could lead to improving cancer treatment. The AMCP Partnership Forum titled "Driving Value and Outcomes in Oncology" and the development of this report were supported by AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Foundation Medicine, IntrinsiQ Specialty Solutions, Janssen Oncology and Johnson and Johnson Health Systems, Eli Lilly and Company, National Pharmaceutical Council, Novartis Pharmaceuticals Corporation, Pharmaceutical Research and Manufacturers of America, Sanofi, Takeda Oncology, and Xcenda.

GOLDRUSH. II. Clustering of galaxies at z ˜ 4-6 revealed with the half-million dropouts over the 100 deg2 area corresponding to 1 Gpc3

NASA Astrophysics Data System (ADS)

Harikane, Yuichi; Ouchi, Masami; Ono, Yoshiaki; Saito, Shun; Behroozi, Peter; More, Surhud; Shimasaku, Kazuhiro; Toshikawa, Jun; Lin, Yen-Ting; Akiyama, Masayuki; Coupon, Jean; Komiyama, Yutaka; Konno, Akira; Lin, Sheng-Chieh; Miyazaki, Satoshi; Nishizawa, Atsushi J.; Shibuya, Takatoshi; Silverman, John

2018-01-01

We present clustering properties from 579492 Lyman-break galaxies (LBGs) at z ˜ 4-6 over the 100 deg2 sky (corresponding to a 1.4 Gpc3 volume) identified in early data of the Hyper Suprime-Cam (HSC) Subaru Strategic Program survey. We derive angular correlation functions (ACFs) for the HSC LBGs with unprecedentedly high statistical accuracies at z ˜ 4-6, and compare them with the halo occupation distribution (HOD) models. We clearly identify significant ACF excesses in 10″ < θ < 90″, the transition scale between one- and two-halo terms, suggestive of the existence of the non-linear halo bias effect. Combining the HOD models and previous clustering measurements of faint LBGs at z ˜ 4-7, we investigate the dark matter halo mass (Mh) of the z ˜ 4-7 LBGs and its correlation with various physical properties including the star formation rate (SFR), the stellar-to-halo mass ratio (SHMR), and the dark matter accretion rate (\\dot{M}_{ h}) over a wide mass range of Mh/M⊙ = 4 × 1010-4 × 1012. We find that the SHMR increases from z ˜ 4 to 7 by a factor of ˜4 at Mh ≃ 1 × 1011 M⊙ , while the SHMR shows no strong evolution in the similar redshift range at Mh ≃ 1 × 1012 M⊙ . Interestingly, we identify a tight relation of SFR/\\dot{M}_{ h}-Mh showing no significant evolution beyond 0.15 dex in this wide mass range over z ˜ 4-7. This weak evolution suggests that the SFR/\\dot{M}_{ h}-Mh relation is a fundamental relation in high-redshift galaxy formation whose star formation activities are regulated by the dark matter mass assembly. Assuming this fundamental relation, we calculate the cosmic star formation rate densities (SFRDs) over z = 0-10 (a.k.a. the Madau-Lilly plot). The cosmic SFRD evolution based on the fundamental relation agrees with the one obtained by observations, suggesting that the cosmic SFRD increase from z ˜ 10 to 4 - 2 (decrease from z ˜ 4-2 to 0) is mainly driven by the increase of the halo abundance (the decrease of the accretion rate).

What can we learn about Mars from satellite magnetic field measurements?

NASA Astrophysics Data System (ADS)

Morschhauser, A.; Mittelholz, A.; Thomas, P.; Vervelidou, F.; Grott, M.; Johnson, C.; Lesur, V.; Lillis, R. J.

2017-12-01

The Mars orbiters MGS and MAVEN provide vector magnetic field data for Mars at a variety of altitudes, locations, and local times. In spite of the abundance of data, there are many open questions concerning the crustal magnetic field of Mars. In this contribution, we present our efforts to estimate the shutdown time of the Martian core dynamo and to estimate Martian paleopole locations, using magnetic field satellite data and models derived from these data [1]. Models are primarily based on MGS data, and we shortly present our recent advances to include MAVEN data. There exists some controversy concerning the timing of the Martian core dynamo shutdown [e.g., 2-5]. We address this question by studying the so-called visible magnetization [6-7] of impact craters larger than 400 km in diameter, and conclude that the dynamo ceased to operate in the Noachian period [8]. Further, paleopole locations have been used to constrain the dynamics of the Martian core dynamo [e.g. 4-5, 9]. However, such estimates are limited by the inherent non-uniqueness of inferring magnetization from magnetic field measurements. Here, we discuss how estimated paleopoles are influenced by this non-uniqueness and the limited signal-to-noise ratio of satellite measurements [6]. Furthermore, we discuss how paleopole locations may still be obtained from satellite magnetic field measurements. In this context, we present some new paleopole estimates for Mars including estimates of uncertainties. References: [1] A. Morschhauser et al. (2014), JGR, doi: 10.1002/2013JE004555 [2] R.J. Lillis et al. (2015), JGR, doi: 10.1002/2014je004774 [3] L.L. Hood et al. (2010), Icarus, doi: 10.1016/j.icarus.2010.01.009 [4] C. Milbury et al. (2012), JGR, doi: 10.1029/2012JE004099 [5] B. Langlais and M. Purucker (2007), PSS, 10.1016/j.pss.2006.03.008 [6] F. Vervelidou et al., On the accuracy of paleopole estimations from magnetic field measurements, GJI, under revision 2017 [7] D. Gubbins et al. (2011), GJI, doi: 10.1111/j.1365-246X.2011.05153.x [8] B. Langlais and M. Purucker (2007), PSS, 10.1016/j.pss.2006.03.008 [8] F. Vervelidou et al., Constraining the date of the martian dynamo shutdown by means of craters' magnetization signatures, JGR, submitted 2017 [9] J. Arkani-Hamed and D. Boutin (2004), JGR, 10.1029/2003JE002229

A novel derivative of doxorubicin, AD198, inhibits canine transitional cell carcinoma and osteosarcoma cells in vitro.

PubMed

Rathore, Kusum; Cekanova, Maria

2015-01-01

Doxorubicin (DOX) is one of the most commonly used chemotherapeutic treatments for a wide range of cancers. N-benzyladriamycin-14-valerate (AD198) is a lipophilic anthracycline that has been shown to target conventional and novel isoforms of protein kinase C (PKC) in cytoplasm of cells. Because of the adverse effects of DOX, including hair loss, nausea, vomiting, liver dysfunction, and cardiotoxicity, novel derivatives of DOX have been synthesized and validated. In this study, we evaluated the effects of DOX and its derivative, AD198, on cell viability of three canine transitional cell carcinoma (K9TCC) (K9TCC#1-Lillie, K9TCC#2-Dakota, K9TCC#4-Molly) and three canine osteosarcoma (K9OSA) (K9OSA#1-Zoe, K9OSA#2-Nashville, K9OSA#3-JJ) primary cancer cell lines. DOX and AD198 significantly inhibited cell proliferation in all tested K9TCC and K9OSA cell lines in a dose-dependent manner. AD198 inhibited cell viability of tested K9TCC and K9OSA cell lines more efficiently as compared to DOX at the same concentration using MTS (3-(4,5-dimethyl-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2h-tetrazolium) assay. AD198 had lower IC50 values as compared to DOX for all tested K9TCC and K9OSA cell lines. In addition, AD198 increased apoptosis in all tested K9TCC and K9OSA cell lines. AD198 increased the caspase activity in tested K9TCC and K9OSA cell lines, which was confirmed by caspase-3/7 assay, and cleavage of poly (ADP-ribose) polymerase (PARP) was confirmed by Western blotting analysis. In addition, AD198 cleaved PKC-δ, which subsequently activated the p38 signaling pathway, resulting in the apoptosis of tested K9TCC and K9OSA cell lines. Inhibition of the p38 signaling pathway by SB203580 rescued DOX- and AD198-induced apoptosis in tested K9TCC and K9OSA cell lines. Our in vitro results suggest that AD198 might be considered as a new treatment option for K9TCC and K9OSA cell lines cancers in vivo.

Personalizing mammography by breast density and other risk factors for breast cancer: analysis of health benefits and cost-effectiveness.

PubMed

Schousboe, John T; Kerlikowske, Karla; Loh, Andrew; Cummings, Steven R

2011-07-05

Current guidelines recommend mammography every 1 or 2 years starting at age 40 or 50 years, regardless of individual risk for breast cancer. To estimate the cost-effectiveness of mammography by age, breast density, history of breast biopsy, family history of breast cancer, and screening interval. Markov microsimulation model. Surveillance, Epidemiology, and End Results program, Breast Cancer Surveillance Consortium, and the medical literature. U.S. women aged 40 to 49, 50 to 59, 60 to 69, and 70 to 79 years with initial mammography at age 40 years and breast density of Breast Imaging Reporting and Data System (BI-RADS) categories 1 to 4. Lifetime. National health payer. Mammography annually, biennially, or every 3 to 4 years or no mammography. Costs per quality-adjusted life-year (QALY) gained and number of women screened over 10 years to prevent 1 death from breast cancer. Biennial mammography cost less than $100,000 per QALY gained for women aged 40 to 79 years with BI-RADS category 3 or 4 breast density or aged 50 to 69 years with category 2 density; women aged 60 to 79 years with category 1 density and either a family history of breast cancer or a previous breast biopsy; and all women aged 40 to 79 years with both a family history of breast cancer and a previous breast biopsy, regardless of breast density. Biennial mammography cost less than $50,000 per QALY gained for women aged 40 to 49 years with category 3 or 4 breast density and either a previous breast biopsy or a family history of breast cancer. Annual mammography was not cost-effective for any group, regardless of age or breast density. Mammography is expensive if the disutility of false-positive mammography results and the costs of detecting nonprogressive and nonlethal invasive cancer are considered. Results are not applicable to carriers of BRCA1 or BRCA2 mutations. Mammography screening should be personalized on the basis of a woman's age, breast density, history of breast biopsy, family history of breast cancer, and beliefs about the potential benefit and harms of screening. Eli Lilly, Da Costa Family Foundation for Research in Breast Cancer Prevention of the California Pacific Medical Center, and Breast Cancer Surveillance Consortium.

Wind field near complex terrain using numerical weather prediction model

NASA Astrophysics Data System (ADS)

Chim, Kin-Sang

The PennState/NCAR MM5 model was modified to simulate an idealized flow pass through a 3D obstacle in the Micro- Alpha Scale domain. The obstacle used were the idealized Gaussian obstacle and the real topography of Lantau Island of Hong Kong. The Froude number under study is ranged from 0.22 to 1.5. Regime diagrams for both the idealized Gaussian obstacle and Lantau island were constructed. This work is divided into five parts. The first part is the problem definition and the literature review of the related publications. The second part briefly discuss as the PennState/NCAR MM5 model and a case study of long- range transport is included. The third part is devoted to the modification and the verification of the PennState/NCAR MM5 model on the Micro-Alpha Scale domain. The implementation of the Orlanski (1976) open boundary condition is included with the method of single sounding initialization of the model. Moreover, an upper dissipative layer, Klemp and Lilly (1978), is implemented on the model. The simulated result is verified by the Automatic Weather Station (AWS) data and the Wind Profiler data. Four different types of Planetary Boundary Layer (PBL) parameterization schemes have been investigated in order to find out the most suitable one for Micro-Alpha Scale domain in terms of both accuracy and efficiency. Bulk Aerodynamic type of PBL parameterization scheme is found to be the most suitable PBL parameterization scheme. Investigation of the free- slip lower boundary condition is performed and the simulated result is compared with that with friction. The fourth part is the use of the modified PennState/NCAR MM5 model for an idealized flow simulation. The idealized uniform flow used is nonhydrostatic and has constant Froude number. Sensitivity test is performed by varying the Froude number and the regime diagram is constructed. Moreover, nondimensional drag is found to be useful for regime identification. The model result is also compared with the analytic results by Miles (1969) and Smith (1980, 1985), and the numerical results of Stein (1992), Miranda and James (1992) and Olaffson and Bougeault (1997). It is found that the simulated result in the present study is comparable with others. The fifth part is the construction of the regime diagram for the Lantau island of Hong Kong. All eight major wind directions are discussed.

Ease of use and patient preference injection simulation study comparing two prefilled insulin pens.

PubMed

Clark, Paula E; Valentine, Virginia; Bodie, Jennifer N; Sarwat, Samiha

2010-07-01

To determine patient ease of use and preference for the Humalog KwikPen* (prefilled insulin lispro [Humalog dagger] pen, Eli Lilly and Company, Indianapolis, IN, USA) (insulin lispro pen) versus the Next Generation FlexPen double dagger (prefilled insulin aspart [NovoRapid section sign ] pen, Novo Nordisk A/S, Bagsvaerd, Denmark) (insulin aspart pen). This was a randomized, open-label, 2-period, 8-sequence crossover study in insulin pen-naïve patients with diabetes. Randomized patients (N = 367) received device training, then simulated low- (15 U) and high- (60 U) dose insulin injections with an appliance. Patients rated pens using an ease of use questionnaire and were asked separately for final pen preferences. The Insulin Device 'Ease of Use' Battery is a 10-item questionnaire with a 7-point scale (higher scores reflect greater ease of use). The primary objective was to determine pen preference for 'easy to press to inject my dose' (by comparing composite scores [low- plus high-dose]). Secondary objectives were to determine pen preference on select questionnaire items (from composite scores), final pen preference, and summary responses for all questionnaire items. On the primary endpoint, 'easy to press to inject my dose,' a statistically significant majority of patients with a preference chose the insulin lispro pen over the insulin aspart pen (68.4%, 95% CI = 62.7-73.6%). Statistically significant majorities of patients with a preference also favored the insulin lispro pen on secondary items: 'easy to hold in my hand when I inject' (64.9%, 95% CI = 58.8-70.7%), 'easy to use when I am in a public place' (67.5%, 95% CI = 61.0-73.6%), and 'overall easy to use' (69.9%, 95% CI = 63.9-75.4%). A statistically significant majority of patients had a final preference for the insulin lispro pen (67.3%, 95% CI = 62.2-72.1%). Among pen-naïve patients with diabetes who had a preference, the majority preferred the insulin lispro pen over the insulin aspart pen with regard to ease of use. Study limitations included open-label design and injection simulation, use of an unvalidated questionnaire, and enrollment of mostly insulin-naïve patients.

Especially for High School Teachers

NASA Astrophysics Data System (ADS)

Howell, J. Emory

1999-07-01

Secondary School Feature Articles * Super Science Connections, by Patricia B. McKean, p 916 * A pHorseshoe, by Roger Plumsky, p 935 National Conferences in Your Part of the Country For the past several months, considerable space in this column has been devoted to forthcoming national conferences and conventions and to highlights of conferences past. For some of us, location is fairly unimportant; but for most of us travel costs and time are both factors to consider when choosing a conference. The community of high school chemistry teachers is favored by the number of national conventions and conferences that are held each year in different locations. In 1999, for example, the spring National Meeting of the American Chemical Society was in Anaheim and the National Science Teachers Association National Convention was in Boston. This summer CHEMED '99 will be held in Fairfield, CT, August 1-5, and the fall National ACS Meeting will be in New Orleans. Teachers from the mid-South especially should consider attending the High School Program at New Orleans, described below by Lillie Tucker Akin, Chairperson of the Division's High School Program Committee. The event will be held on Sunday to minimize conflicts with the beginning of the school year. JCE at CHEMED '99 Stop by the JCE booth at CHEMED '99 in the exhibits area to learn more about the wide array of print and nonprint resources you can use in your classroom and laboratory. Members of the editorial staff will be on hand to talk with you. You are invited to participate in a workshop, "Promoting Active Learning through JCE Activity Sheets and Software", on Monday, August 1, 8:30-10:30. The free hands-on workshop is number WT11 and we encourage you to include it among your choices in the blanks provided on the third page of the registration form. We will also conduct an interactive session to listen to ideas for making the Journal more useful to you. Check the final program for location and time or inquire at the JCE exhibit booth. NSTA in Boston For the representatives of the Journal, the highlight of the National Science Teachers Association Convention was visiting with the many readers who stopped by the JCE booth. Among them were several who have authored an article or reviewed manuscripts. We hope that number increases from year to year. JCE exists for its readers and because many readers are willing to devote the time and effort necessary to write a manuscript and revise it based on peer review. The convention offered such a variety of opportunities to acquire useful information that it is impossible to name a single highlight, or even to list the top ten. Representative of the many outstanding chemistry-oriented sessions presented by high school teachers were "Ultraviolet, Visible and Infrared Spectroscopy in the Chemistry and Physics Laboratory", "Kool Conversions in a Block Schedule", and "Hot Packs, Cold Packs, and a Six-Pack of Chemistry Projects". Reports from Other Journals On pages 882-885, Steve Long and Kathy Thorsen have summarized interesting articles that have appeared recently in The Science Teacher and Chem 13 News, respectively. Even if you are a regular reader of one or both of these journals, you will enjoy reading these summaries. Steve and Kathy have done a great job of highlighting interesting and useful information. I thank both of them for these fine contributions to the Journal. High School Day in New Orleans Mark August 22, 1999, on your calendar now and plan to attend High School Chemistry Day at the National ACS Meeting in New Orleans. The High School Program Committee, with support from local ACS sections, has planned an extravaganza of workshops and presentations, including environmental programs and workshops conducted by Sargent-Welch; an afternoon of instrumentation by Buck Laboratories with the Alabama Science in Motion vans and drivers to show how to transport chemistry on wheels; 12 demonstrations by nationally recognized chemical demonstration experts; a series of nine oral presentations on "hot" topics in chemistry today; Carolina Biological's showcasing of Chemistry Set to Music and demonstrations where you can watch the periodic table come to life in front of your eyes; an afternoon of safety by Kauffman and Associates; and Penny Sconzo's entire day on calculator literacy in chemistry and biology with sessions for beginners and advanced users. In addition to five concurrent sessions specifically for high school teachers, the Division of Chemical Education will offer a variety of programs throughout the conference. A high school-college interface luncheon will feature chemical educator Glenn Crosby as keynote speaker. An array of door prizes will be given away, including a crisp 100 bill. Tickets for the luncheon are limited and will only be sold through preregistration. Registration information can be obtained through the ACS Internet home page, http://www.acs.org, in Chemical and Engineering News, or in the summer issue of the Division of Chemical Education Newsletter. Eisenhower funds can be used as support funds (check with your school coordinator for title programs). There will be a membership registration desk for teachers interested in joining the ACS Division of Chemical Education. Membership dues are 15 per year. We have a lot planned for you and we need all our high school chemistry teachers to attend and make this event a huge success! I look forward to seeing each of you in 'Nawlins! Lillie Tucker Akin

Long-acting insulins alter milk composition and metabolism of lactating dairy cows.

PubMed

Winkelman, L A; Overton, T R

2013-01-01

This study investigated the effect of 2 different types of long-acting insulin on milk production, milk composition, and metabolism in lactating dairy cows. Multiparous cows (n=30) averaging 88 d in milk were assigned to one of 3 treatments in a completely randomized design. Treatments consisted of control (C), Humulin-N (H; Eli Lilly and Company, Indianapolis, IN), and insulin glargine (L). The H and L treatments were administered twice daily at 12-h intervals via subcutaneous injection for 10d. Cows were milked twice daily, and milk composition was determined every other day. Mammary biopsies were conducted on d 11, and mammary proteins extracted from the biopsies were analyzed by Western blot for components of insulin and mammalian target of rapamycin signaling pathways. Treatment had no effect on dry matter intake or milk yield. Treatment with both forms of long-acting insulin increased milk protein content and tended to increase milk protein yield over the 10-d treatment period. Analysis of milk N fractions from samples collected on d 10 of treatment suggested that cows administered L tended to have higher yields of milk protein fractions than cows administered H. Milk fat content and yield tended to be increased for cows administered long-acting insulins. Lactose content and yields were decreased by treatment with long-acting insulins. Administration of long-acting insulins, particularly L, tended to shift milk fatty acid composition toward increased short- and medium-chain fatty acids and decreased long-chain fatty acids. Plasma concentrations of glucose and urea N were lower for cows administered long-acting insulins; interactions of treatment and sampling time were indicative of more pronounced effects of L than H on these metabolites. Concentrations of nonesterified fatty acids and insulin were increased in cows administered long-acting insulins. Decreased concentrations of urea N in both plasma and milk suggested more efficient use of N in cows administered long-acting insulins. Western blot analysis of mammary tissue collected by biopsy indicated that the ratios of phosphorylated protein kinase b (Akt) to total Akt and phosphorylated ribosomal protein S6 (rpS6) to total rpS6 were not affected by long-acting insulins. Modestly elevating insulin activity in lactating dairy cows using long-acting insulins altered milk composition and metabolism. Future research should explore mechanisms by which either insulin concentrations or insulin signaling pathways in the mammary gland can be altered to enhance milk fat and protein production. Copyright © 2013 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

Phase 3 trials of solanezumab for mild-to-moderate Alzheimer's disease.

PubMed

Doody, Rachelle S; Thomas, Ronald G; Farlow, Martin; Iwatsubo, Takeshi; Vellas, Bruno; Joffe, Steven; Kieburtz, Karl; Raman, Rema; Sun, Xiaoying; Aisen, Paul S; Siemers, Eric; Liu-Seifert, Hong; Mohs, Richard

2014-01-23

Alzheimer's disease is characterized by amyloid-beta plaques, neurofibrillary tangles, gliosis, and neuronal loss. Solanezumab, a humanized monoclonal antibody, preferentially binds soluble forms of amyloid and in preclinical studies promoted its clearance from the brain. In two phase 3, double-blind trials (EXPEDITION 1 and EXPEDITION 2), we randomly assigned 1012 and 1040 patients, respectively, with mild-to-moderate Alzheimer's disease to receive placebo or solanezumab (administered intravenously at a dose of 400 mg) every 4 weeks for 18 months. The primary outcomes were the changes from baseline to week 80 in scores on the 11-item cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog11; range, 0 to 70, with higher scores indicating greater cognitive impairment) and the Alzheimer's Disease Cooperative Study-Activities of Daily Living scale (ADCS-ADL; range, 0 to 78, with lower scores indicating worse functioning). After analysis of data from EXPEDITION 1, the primary outcome for EXPEDITION 2 was revised to the change in scores on the 14-item cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog14; range, 0 to 90, with higher scores indicating greater impairment), in patients with mild Alzheimer's disease. Neither study showed significant improvement in the primary outcomes. The modeled difference between groups (solanezumab group minus placebo group) in the change from baseline was -0.8 points for the ADAS-cog11 score (95% confidence interval [CI], -2.1 to 0.5; P=0.24) and -0.4 points for the ADCS-ADL score (95% CI, -2.3 to 1.4; P=0.64) in EXPEDITION 1 and -1.3 points (95% CI, -2.5 to 0.3; P=0.06) and 1.6 points (95% CI, -0.2 to 3.3; P=0.08), respectively, in EXPEDITION 2. Between-group differences in the changes in the ADAS-cog14 score were -1.7 points in patients with mild Alzheimer's disease (95% CI, -3.5 to 0.1; P=0.06) and -1.5 in patients with moderate Alzheimer's disease (95% CI, -4.1 to 1.1; P=0.26). In the combined safety data set, the incidence of amyloid-related imaging abnormalities with edema or hemorrhage was 0.9% with solanezumab and 0.4% with placebo for edema (P=0.27) and 4.9% and 5.6%, respectively, for hemorrhage (P=0.49). Solanezumab, a humanized monoclonal antibody that binds amyloid, failed to improve cognition or functional ability. (Funded by Eli Lilly; EXPEDITION 1 and 2 ClinicalTrials.gov numbers, NCT00905372 and NCT00904683.).

Learn, how to learn

NASA Astrophysics Data System (ADS)

Narayanan, M.

2002-12-01

Ernest L. Boyer, in his 1990 book, "Scholarship Reconsidered: Priorities of the Professorate" cites some ground breaking studies and offers a new paradigm that identifies the need to recognize the growing conversation about teaching, scholarship and research in the Universities. The use of `ACORN' model suggested by Hawkins and Winter to conquer and mastering change, may offer some helpful hints for the novice professor, whose primary objective might be to teach students to `learn how to learn'. Action : It is possible to effectively change things only when a teaching professor actually tries out a new idea. Communication : Changes are successful only when the new ideas effectively communicated and implemented. Ownership : Support for change is extremely important and is critical. Only strong commitment for accepting changes demonstrates genuine leadership. Reflection : Feedback helps towards thoughtful evaluation of the changes implemented. Only reflection can provide a tool for continuous improvement. Nurture : Implemented changes deliver results only when nurtured and promoted with necessary support systems, documentation and infrastructures. Inspired by the ACORN model, the author experimented on implementing certain principles of `Total Quality Management' in the classroom. The author believes that observing the following twenty principles would indeed help the student learners how to learn, on their own towards achieving the goal of `Lifelong Learning'. The author uses an acronym : QUOTES : Quality Underscored On Teaching Excellence Strategy, to describe his methods for improving classroom teacher-learner participation. 1. Break down all barriers. 2. Create consistency of purpose with a plan. 3. Adopt the new philosophy of quality. 4. Establish high Standards. 5. Establish Targets / Goals. 6. Reduce dependence on Lectures. 7. Employ Modern Methods. 8. Control the Process. 9. Organize to reach goals. 10. Prevention vs. Correction. 11. Periodic Improvements. 12. Maintain Momentum. 13. Feedback : Communication. 14. Fact - Based Decisions. 15. Exploit Opportunities. 16. Mobilization of Expertise. 17. Drive out Fear. 18. Recognition / Keep Score. 19. Identify Accomplishments. 20. Customer Focus / Results. In conclusion, the author believes that the ACORN model and the QUOTES model may offer some guidelines that would help and enable the instructor to motivate learners to learn on their own. References Boyer, Ernest L. (1990). Scholarship reconsidered: Priorities of the Professorate. Princeton, NJ: Carnegie Foundation for the Advancement of Teaching. Hawkins, P., and Winter, J. (1997). Mastering change: Learning the lessons of the enterprise in higher education initiative. London: Department for Education and Employment. Narayanan, Mysore (2002). Total Quality Management (TQM) and the Teaching Professor. Oxford, Ohio. : Mimi University : 22nd Annual Lilly Conference on College Teaching.

Fasting glucose measurement as a potential first step screening for glucose metabolism abnormalities in women with anovulatory polycystic ovary syndrome.

PubMed

Veltman-Verhulst, Susanne M; Goverde, Angelique J; van Haeften, Timon W; Fauser, Bart C J M

2013-08-01

Is routine screening by oral glucose tolerance test (OGTT) needed for all women with polycystic ovary syndrome (PCOS)? Screening for glucose metabolism abnormalities of PCOS patients by an OGTT could potentially be limited to patients who present with a fasting glucose concentration between 6.1 and 7.0 mmol/l only. Women with PCOS are at increased risk of developing diabetes. This study proposes a stepwise screening strategy for (pre)diabetes for PCOS patients based on risk stratification by fasting plasma glucose. A cross-sectional study of 226 women diagnosed with anovulatory PCOS. A consecutive series of 226 patients, diagnosed with PCOS at the University Medical Centre Utrecht, the Netherlands, were screened for glucose metabolism abnormalities by OGTT (75 g glucose load). The majority of the 226 women (mean age: 29.6 ± 4.3 years; BMI: 27.3 ± 6.7 kg/m(2); 81% Caucasian) presented with a normal OGTT (169 women (75%)). Of the 57 (25%) women presenting with mild to moderate glucose abnormalities, 53 (93%) could be identified by fasting glucose concentrations only. Diabetes was diagnosed in a total of eight women (3.5%). In six women, the diagnosis was based on fasting glucose >7.0 mmol/l. The other two cases of diabetes initially presented with fasting glucose between 6.1 and 7.0 mmol/l and were diagnosed by OGTT assessment. No women diagnosed with diabetes presented with fasting glucose levels below 6.1 mmol/l. We therefore conclude that all diabetes patients could potentially be found by initial fasting glucose assessment followed by OGTT only in patients with fasting glucose between 6.1 and 7.0 mmol/l. Before general implementation can be advised, this screening algorithm should be validated in a prospective study of a similar or greater number of PCOS women. Our study comprised of a mostly Caucasian (81%) population, therefore generalization to other ethnic populations should be done with caution. No external finance was involved in this study. B.C.J.M.F. has received fees and grant support from the following companies (in alphabetic order); Andromed, Ardana, Ferring, Genovum, Merck Serono, MSD, Organon, Pantharei Bioscience, PregLem, Schering, Schering Plough, Serono and Wyeth. A.J.G. has received fees from Abbott, Bayer Schering and IBSA. T.W.H. has received fees from Merck, Sharpe & Dohme, GlaxoSmithKline, NovoNordisk and Eli Lilly. The authors declare complete independence from funders. NCT00821379.

The Mechanics of Impact Basin Formation: Comparisons between Modeling and Geophysical Observations

NASA Astrophysics Data System (ADS)

Stewart, S. T.

2010-12-01

Impact basins are the largest geologic structures on planetary surfaces. Single or multiple ring-shaped scarps or arcuate chains of massifs typically surround basin-sized craters (e.g., larger than about 300 km diameter on the moon [1]). Impact basins also possess central mass anomalies related to ejection of a portion of the crust (and mantle) and uplift of the mantle. I will discuss insights into the mechanics of impact basin formation derived from numerical simulations and focus on features that may be compared with gravity and topography data. The simulations of basin formation use the method of [2] with an improved rheological model that includes dynamic weakening of faults and more accurate treatment of the mantle solidus. Two-dimensional simulations of vertical impacts onto spherical planets utilize a central gravity field, and three-dimensional simulations of oblique impacts include a self-gravity calculation. During the opening and collapse of the transient crater, localization of strain leads to deformation features that are interpreted as deep faults through the lithosphere. Based on simulations of mantle-excavating impacts onto the moon and Mars with thermal gradients that intersect the solidus in the asthenosphere, the final impact structure has three major features: (i) an inner basin filled with melt and bounded by the folded lithosphere, (ii) a broad shallow terrace of faulted and translated lithosphere with an ejecta deposit, and (iii) the surrounding autochthonous lithosphere with radially thinning ejecta. The folded lithosphere is a complex structure that experiences translation inward and then outward again during collapse of the transient cavity. The uplifted mantle within this structure is overlain by a thin layer of hot crustal material. In addition to asymmetry in the excavated material, 45-degree impact events produce an asymmetric terrace feature. The principal observations for comparison to the calculations are the inferred locations of major ring structures (derived from topography and geologic mapping) and the crustal thickness and mantle topography (derived from gravity and topography) [see also 3]. Preliminary comparisons indicate that the simulations produce the major features in the observations. I will present detailed comparisons between simulations and observations for major basins on the moon, including South Pole-Aitken, for different initial lithospheric thicknesses and thermal gradients. [1] Spudis, P.D. (1993) The Geology of Multi-Ring Impact basins: Cambridge University Press. [2] Senft, L.E. and S.T. Stewart (2009) Earth and Planetary Science Letters 287, 471-482. [3] Lillis, R.J., et al. (2010) AGU Fall Meeting.

Cost minimization analysis of different growth hormone pen devices based on time-and-motion simulations

PubMed Central

2010-01-01

Background Numerous pen devices are available to administer recombinant Human Growth Hormone (rhGH), and both patients and health plans have varying issues to consider when selecting a particular product and device for daily use. Therefore, the present study utilized multi-dimensional product analysis to assess potential time involvement, required weekly administration steps, and utilization costs relative to daily rhGH administration. Methods Study objectives were to conduct 1) Time-and-Motion (TM) simulations in a randomized block design that allowed time and steps comparisons related to rhGH preparation, administration and storage, and 2) a Cost Minimization Analysis (CMA) relative to opportunity and supply costs. Nurses naïve to rhGH administration and devices were recruited to evaluate four rhGH pen devices (2 in liquid form, 2 requiring reconstitution) via TM simulations. Five videotaped and timed trials for each product were evaluated based on: 1) Learning (initial use instructions), 2) Preparation (arrange device for use), 3) Administration (actual simulation manikin injection), and 4) Storage (maintain product viability between doses), in addition to assessment of steps required for weekly use. The CMA applied micro-costing techniques related to opportunity costs for caregivers (categorized as wages), non-drug medical supplies, and drug product costs. Results Norditropin® NordiFlex and Norditropin® NordiPen (NNF and NNP, Novo Nordisk, Inc., Bagsværd, Denmark) took less weekly Total Time (p < 0.05) to use than either of the comparator products, Genotropin® Pen (GTP, Pfizer, Inc, New York, New York) or HumatroPen® (HTP, Eli Lilly and Company, Indianapolis, Indiana). Time savings were directly related to differences in new package Preparation times (NNF (1.35 minutes), NNP (2.48 minutes) GTP (4.11 minutes), HTP (8.64 minutes), p < 0.05)). Administration and Storage times were not statistically different. NNF (15.8 minutes) and NNP (16.2 minutes) also took less time to Learn than HTP (24.0 minutes) and GTP (26.0 minutes), p < 0.05). The number of weekly required administration steps was also least with NNF and NNP. Opportunity cost savings were greater in devices that were easier to prepare for use; GTP represented an 11.8% drug product savings over NNF, NNP and HTP at time of study. Overall supply costs represented <1% of drug costs for all devices. Conclusions Time-and-motion simulation data used to support a micro-cost analysis demonstrated that the pen device with the greater time demand has highest net costs. PMID:20377905

Cost minimization analysis of different growth hormone pen devices based on time-and-motion simulations.

PubMed

Nickman, Nancy A; Haak, Sandra W; Kim, Jaewhan

2010-04-08

Numerous pen devices are available to administer recombinant Human Growth Hormone (rhGH), and both patients and health plans have varying issues to consider when selecting a particular product and device for daily use. Therefore, the present study utilized multi-dimensional product analysis to assess potential time involvement, required weekly administration steps, and utilization costs relative to daily rhGH administration. Study objectives were to conduct 1) Time-and-Motion (TM) simulations in a randomized block design that allowed time and steps comparisons related to rhGH preparation, administration and storage, and 2) a Cost Minimization Analysis (CMA) relative to opportunity and supply costs. Nurses naïve to rhGH administration and devices were recruited to evaluate four rhGH pen devices (2 in liquid form, 2 requiring reconstitution) via TM simulations. Five videotaped and timed trials for each product were evaluated based on: 1) Learning (initial use instructions), 2) Preparation (arrange device for use), 3) Administration (actual simulation manikin injection), and 4) Storage (maintain product viability between doses), in addition to assessment of steps required for weekly use. The CMA applied micro-costing techniques related to opportunity costs for caregivers (categorized as wages), non-drug medical supplies, and drug product costs. Norditropin(R) NordiFlex and Norditropin(R) NordiPen (NNF and NNP, Novo Nordisk, Inc., Bagsvaerd, Denmark) took less weekly Total Time (p < 0.05) to use than either of the comparator products, Genotropin(R) Pen (GTP, Pfizer, Inc, New York, New York) or HumatroPen(R) (HTP, Eli Lilly and Company, Indianapolis, Indiana). Time savings were directly related to differences in new package Preparation times (NNF (1.35 minutes), NNP (2.48 minutes) GTP (4.11 minutes), HTP (8.64 minutes), p < 0.05)). Administration and Storage times were not statistically different. NNF (15.8 minutes) and NNP (16.2 minutes) also took less time to Learn than HTP (24.0 minutes) and GTP (26.0 minutes), p < 0.05). The number of weekly required administration steps was also least with NNF and NNP. Opportunity cost savings were greater in devices that were easier to prepare for use; GTP represented an 11.8% drug product savings over NNF, NNP and HTP at time of study. Overall supply costs represented <1% of drug costs for all devices. Time-and-motion simulation data used to support a micro-cost analysis demonstrated that the pen device with the greater time demand has highest net costs.

The Direct Cost of Managing a Rare Disease: Assessing Medical and Pharmacy Costs Associated with Duchenne Muscular Dystrophy in the United States.

PubMed

Thayer, Sarah; Bell, Christopher; McDonald, Craig M

2017-06-01

A Duchenne muscular dystrophy (DMD) cohort was identified using a claims-based algorithm to estimate health care utilization and costs for commercially insured DMD patients in the United States. Previous analyses have used broad diagnosis codes that include a range of muscular dystrophy types as a proxy to estimate the burden of DMD. To estimate DMD-associated resource utilization and costs in a sample of patients identified via a claims-based algorithm using diagnosis codes, pharmacy prescriptions, and procedure codes unique to DMD management based on DMD clinical milestones. DMD patients were selected from a commercially insured claims database (2000-2009). Patients with claims suggestive of a non-DMD diagnosis or who were aged 30 years or older were excluded. Each DMD patient was matched by age, gender, and region to controls without DMD in a 1:10 ratio (DMD patients n = 75; controls n = 750). All-cause health care resource utilization, including emergency department, inpatient, outpatient, and physician office visits, and all-cause health care costs were examined over a minimum 1-year period. Costs were computed as total health-plan and patient-paid amounts of adjudicated medical claims (in annualized U.S. dollars). The average age of the DMD cohort was 13 years. Patients in the DMD cohort had a 10-fold increase in health care costs compared with controls ($23,005 vs. $2,277, P < 0.001). Health care costs were significantly higher for the DMD cohort across age strata and, in particular, for DMD patients aged 14-29 years ($40,132 vs. $2,746, P < 0.001). In the United States, resource use and medical costs of DMD are substantial and increase with age. Funding for this study (GHO-10-4441) was provided by GlaxoSmithKline (GSK). Optum was contracted by GSK to conduct the study. Thayer was an employee of Optum Health Economics and Outcomes Research at the time of this study and was not compensated for her participation as an author of this manuscript. Bell is an employee and shareholder of GSK. McDonald has been a consultant for GSK, Sarepta, PTC Therapeutics, Biomarin, and Catabasis on clinical trials regarding Duchenne muscular dystrophy clinical trial design, endpoint selection, and data analysis; Mitobridge for drug development; and Eli Lilly as part of a steering committee for clinical trials. Study concept and design were contributed primarily by Bell, along with Thayer and McDonald. Thayer collected the data, and data interpretation was performed by Thayer and Bell, along with McDonald. The manuscript was written by Thayer and Bell, along with McDonald, and revised by all the authors.

Ixekizumab for the treatment of patients with active psoriatic arthritis and an inadequate response to tumour necrosis factor inhibitors: results from the 24-week randomised, double-blind, placebo-controlled period of the SPIRIT-P2 phase 3 trial.

PubMed

Nash, Peter; Kirkham, Bruce; Okada, Masato; Rahman, Proton; Combe, Benard; Burmester, Gerd-Ruediger; Adams, David H; Kerr, Lisa; Lee, Chin; Shuler, Catherine L; Genovese, Mark

2017-06-10

Patients who have had inadequate response to tumour necrosis factor inhibitors have fewer treatment options and are generally more treatment refractory to subsequent therapeutic interventions than previously untreated patients. We report the efficacy and safety of ixekizumab, a monoclonal antibody that selectively targets interleukin-17A, in patients with active psoriatic arthritis and previous inadequate response to tumour necrosis factor inhibitors. In this double-blind, multicentre, randomised, placebo-controlled, phase 3 study (SPIRIT-P2), patients were recruited from 109 centres across ten countries in Asia, Australia, Europe, and North America. Patients were aged 18 years or older, had a confirmed diagnosis of psoriatic arthritis for at least 6 months, and had a previous inadequate response, distinguished by being refractory to therapy or had loss of efficacy, or were intolerant to tumour necrosis factor inhibitors. Patients were randomly assigned (1:1:1) by a computer-generated random sequence to receive a subcutaneous injection of 80 mg ixekizumab every 4 weeks or every 2 weeks after a 160 mg starting dose or placebo. The primary endpoint was the proportion of patients who attained at least 20% improvement in the American College of Rheumatology response criteria (ACR-20) at week 24. This study is registered with ClinicalTrials.gov, number NCT02349295. Between March 3, 2015, to March 22, 2016, 363 patients were randomly assigned to placebo (n=118), ixekizumab every 4 weeks (n=122), or ixekizumab every 2 weeks (n=123). At week 24, a higher proportion of patients attained ACR-20 with ixekizumab every 4 weeks (65 [53%] patients; effect size vs placebo 33·8% [95% CI 22·4-45·2]; p<0·0001) and ixekizumab every 2 weeks (59 [48%] patients; 28.5% [17·1-39.8]; p<0·0001) than did patients with placebo (23 [20%] patients). Up to week 24, serious adverse events were reported in three (3%) patients with ixekizumab every 4 weeks, eight (7%) with ixekizumab every 2 weeks, and four (3%) with placebo; no deaths were reported. Infections were reported in 47 (39%) patients with ixekizumab every 4 weeks, 47 (38%) with ixekizumab every 2 weeks, and 35 (30%) with placebo. Three (2%) serious infections, all in patients in the ixekizumab every 2 weeks group, were reported. Both the 2-week and 4-week ixekizumab dosing regimens improved the signs and symptoms of patients with active psoriatic arthritis and who had previously inadequate response to tumour necrosis factor inhibitors, with a safety profile consistent with previous studies investigating ixekizumab. Eli Lilly and Company. Copyright © 2017 Elsevier Ltd. All rights reserved.

General geology and mines of the East Tintic mining district, Utah and Juab counties, Utah, with sections on the geology of the Burgin mine and the geology of the Trixie mine

USGS Publications Warehouse

Morris, H.T.; Lovering, Thomas Seward; Mogensen, A.P.; Shepard, W.M.; Perry, L.I.; Smith, S.M.

1979-01-01

This report is a study of the rocks, geologic structures, and mines of a highly productive silver, gold, and base-metal mining district in the east-central Great Basin. The East Tintic mining district is in the east-central part of the East Tintic Mountains, near the east margin of the Basin and Range province in Utah and Juab Counties, Utah. The district occupies the northeastern part of the Eureka quadrangle and is about 5 mi (8 km) wide and 6 mi (9.7 km) long. Officially it is within the designated boundaries of the Tintic mining district, but it generally though erroneously has been regarded as a separate district since the late 1800's.Prospecting was first undertaken in East Tintic in 1870; although small quantities of ore were produced in 1899 and from 1909 to 1913, the district first achieved prominence in 1916 with the discovery of the totally concealed Central ore body of the Tintic Standard mine. Within a few years of this discovery, the Tintic Standard became one of the most productive silver mines in the world. Additional discoveries of important concealed ore deposits have continued to be made in the district, including the North Lily mine in 1927, the Eureka Lilly and Eureka Standard mines in 1928, the Burgin mine in 1958, and the Trixie mine in 1969.To December 31, 1975, the East Tintic mining district has yielded approximately 4.83 million short tons (4.38 million tonnes) of silver, gold, and base-metal ores, largely from concealed deposits overlain by many hundreds of feet of barren rocks. These ores have a gross valuation of approximately $231 million. The district first achieved prominence in 1916 with the discovery of the ore bodies of the Tintic Standard mine, which for a time was the world's richest silver producer (Lindgren, 1933, p. 588). By 1946 this deposit and a number of other deposits discovered and developed nearby had been exhausted, and the district became dormant. A dramatic revival of, mining activities in the East Tintic district began in 1956 after the discovery and subsequent development of the concealed Burgin ore bodies in an area 1 mile (1.6 km) southeast of the Tintic Standard that previously had been only superficially prospected. As in the earlier history of the district, the Burgin development has led to the discovery of other concealed deposits, focusing international attention on the revitalization of a nearly abandoned mining district by the application of geologic and geochemical techniques.

Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial.

PubMed

Wilke, Hansjochen; Muro, Kei; Van Cutsem, Eric; Oh, Sang-Cheul; Bodoky, György; Shimada, Yasuhiro; Hironaka, Shuichi; Sugimoto, Naotoshi; Lipatov, Oleg; Kim, Tae-You; Cunningham, David; Rougier, Philippe; Komatsu, Yoshito; Ajani, Jaffer; Emig, Michael; Carlesi, Roberto; Ferry, David; Chandrawansa, Kumari; Schwartz, Jonathan D; Ohtsu, Atsushi

2014-10-01

VEGFR-2 has a role in gastric cancer pathogenesis and progression. We assessed whether ramucirumab, a monoclonal antibody VEGFR-2 antagonist, in combination with paclitaxel would increase overall survival in patients previously treated for advanced gastric cancer compared with placebo plus paclitaxel. This randomised, placebo-controlled, double-blind, phase 3 trial was done at 170 centres in 27 countries in North and South America, Europe, Asia, and Australia. Patients aged 18 years or older with advanced gastric or gastro-oesophageal junction adenocarcinoma and disease progression on or within 4 months after first-line chemotherapy (platinum plus fluoropyrimidine with or without an anthracycline) were randomly assigned with a centralised interactive voice or web-response system in a 1:1 ratio to receive ramucirumab 8 mg/kg or placebo intravenously on days 1 and 15, plus paclitaxel 80 mg/m(2) intravenously on days 1, 8, and 15 of a 28-day cycle. A permuted block randomisation, stratified by geographic region, time to progression on first-line therapy, and disease measurability, was used. The primary endpoint was overall survival. Efficacy analysis was by intention to treat, and safety analysis included all patients who received at least one treatment with study drug. This trial is registered with ClinicalTrials.gov, number NCT01170663, and has been completed; patients who are still receiving treatment are in the extension phase. Between Dec 23, 2010, and Sept 23, 2012, 665 patients were randomly assigned to treatment-330 to ramucirumab plus paclitaxel and 335 to placebo plus paclitaxel. Overall survival was significantly longer in the ramucirumab plus paclitaxel group than in the placebo plus paclitaxel group (median 9·6 months [95% CI 8·5-10·8] vs 7·4 months [95% CI 6·3-8·4], hazard ratio 0·807 [95% CI 0·678-0·962]; p=0·017). Grade 3 or higher adverse events that occurred in more than 5% of patients in the ramucirumab plus paclitaxel group versus placebo plus paclitaxel included neutropenia (133 [41%] of 327 vs 62 [19%] of 329), leucopenia (57 [17%] vs 22 [7%]), hypertension (46 [14%] vs eight [2%]), fatigue (39 [12%] vs 18 [5%]), anaemia (30 [9%] vs 34 [10%]), and abdominal pain (20 [6%] vs 11 [3%]). The incidence of grade 3 or higher febrile neutropenia was low in both groups (ten [3%] vs eight [2%]). The combination of ramucirumab with paclitaxel significantly increases overall survival compared with placebo plus paclitaxel, and could be regarded as a new standard second-line treatment for patients with advanced gastric cancer. Eli Lilly and Company. Copyright © 2014 Elsevier Ltd. All rights reserved.

Large Eddy simulation of turbulence: A subgrid scale model including shear, vorticity, rotation, and buoyancy

NASA Technical Reports Server (NTRS)

Canuto, V. M.

1994-01-01

The Reynolds numbers that characterize geophysical and astrophysical turbulence (Re approximately equals 10(exp 8) for the planetary boundary layer and Re approximately equals 10(exp 14) for the Sun's interior) are too large to allow a direct numerical simulation (DNS) of the fundamental Navier-Stokes and temperature equations. In fact, the spatial number of grid points N approximately Re(exp 9/4) exceeds the computational capability of today's supercomputers. Alternative treatments are the ensemble-time average approach, and/or the volume average approach. Since the first method (Reynolds stress approach) is largely analytical, the resulting turbulence equations entail manageable computational requirements and can thus be linked to a stellar evolutionary code or, in the geophysical case, to general circulation models. In the volume average approach, one carries out a large eddy simulation (LES) which resolves numerically the largest scales, while the unresolved scales must be treated theoretically with a subgrid scale model (SGS). Contrary to the ensemble average approach, the LES+SGS approach has considerable computational requirements. Even if this prevents (for the time being) a LES+SGS model to be linked to stellar or geophysical codes, it is still of the greatest relevance as an 'experimental tool' to be used, inter alia, to improve the parameterizations needed in the ensemble average approach. Such a methodology has been successfully adopted in studies of the convective planetary boundary layer. Experienc e with the LES+SGS approach from different fields has shown that its reliability depends on the healthiness of the SGS model for numerical stability as well as for physical completeness. At present, the most widely used SGS model, the Smagorinsky model, accounts for the effect of the shear induced by the large resolved scales on the unresolved scales but does not account for the effects of buoyancy, anisotropy, rotation, and stable stratification. The latter phenomenon, which affects both geophysical and astrophysical turbulence (e.g., oceanic structure and convective overshooting in stars), has been singularly difficult to account for in turbulence modeling. For example, the widely used model of Deardorff has not been confirmed by recent LES results. As of today, there is no SGS model capable of incorporating buoyancy, rotation, shear, anistropy, and stable stratification (gravity waves). In this paper, we construct such a model which we call CM (complete model). We also present a hierarchy of simpler algebraic models (called AM) of varying complexity. Finally, we present a set of models which are simplified even further (called SM), the simplest of which is the Smagorinsky-Lilly model. The incorporation of these models into the presently available LES codes should begin with the SM, to be followed by the AM and finally by the CM.

Large Eddy simulation of turbulence: A subgrid scale model including shear, vorticity, rotation, and buoyancy

NASA Astrophysics Data System (ADS)

Canuto, V. M.

1994-06-01

The Reynolds numbers that characterize geophysical and astrophysical turbulence (Re approximately equals 108 for the planetary boundary layer and Re approximately equals 1014 for the Sun's interior) are too large to allow a direct numerical simulation (DNS) of the fundamental Navier-Stokes and temperature equations. In fact, the spatial number of grid points N approximately Re9/4 exceeds the computational capability of today's supercomputers. Alternative treatments are the ensemble-time average approach, and/or the volume average approach. Since the first method (Reynolds stress approach) is largely analytical, the resulting turbulence equations entail manageable computational requirements and can thus be linked to a stellar evolutionary code or, in the geophysical case, to general circulation models. In the volume average approach, one carries out a large eddy simulation (LES) which resolves numerically the largest scales, while the unresolved scales must be treated theoretically with a subgrid scale model (SGS). Contrary to the ensemble average approach, the LES+SGS approach has considerable computational requirements. Even if this prevents (for the time being) a LES+SGS model to be linked to stellar or geophysical codes, it is still of the greatest relevance as an 'experimental tool' to be used, inter alia, to improve the parameterizations needed in the ensemble average approach. Such a methodology has been successfully adopted in studies of the convective planetary boundary layer. Experienc e with the LES+SGS approach from different fields has shown that its reliability depends on the healthiness of the SGS model for numerical stability as well as for physical completeness. At present, the most widely used SGS model, the Smagorinsky model, accounts for the effect of the shear induced by the large resolved scales on the unresolved scales but does not account for the effects of buoyancy, anisotropy, rotation, and stable stratification. The latter phenomenon, which affects both geophysical and astrophysical turbulence (e.g., oceanic structure and convective overshooting in stars), has been singularly difficult to account for in turbulence modeling. For example, the widely used model of Deardorff has not been confirmed by recent LES results. As of today, there is no SGS model capable of incorporating buoyancy, rotation, shear, anistropy, and stable stratification (gravity waves). In this paper, we construct such a model which we call CM (complete model). We also present a hierarchy of simpler algebraic models (called AM) of varying complexity. Finally, we present a set of models which are simplified even further (called SM), the simplest of which is the Smagorinsky-Lilly model. The incorporation of these models into the presently available LES codes should begin with the SM, to be followed by the AM and finally by the CM.

Geochronology and geology of late Oligocene through Miocene volcanism and mineralization in the western San Juan Mountains, Colorado

USGS Publications Warehouse

Bove, D.J.; Hon, Ken; Budding, K.E.; Slack, J.F.; Snee, L.W.; Yeoman, R.A.

2000-01-01

Twenty-five new 40Ar/39Ar ages from volcanic rocks and veins in the western San Juan Mountains clarify relationships between volcanism and mineralization in this classic area. Five calc-alkaline ash-flow sheets erupted from caldera sources (Ute Ridge, Blue Mesa, Dillon Mesa, Sapinero Mesa, and Crystal Lake Tuffs) from 28.6 to 27.6 Ma. This is a much more restricted time interval than previously thought and indicates that the underlying batholith rose and evolved very rapidly beneath the western San Juan Mountains. The new ages and geologic relations constrain the timing of joint resurgence of the Uncompahgre and San Juan calderas to between 28.2 and 27.6 Ma. The collapse of the Silverton caldera produced a set of strong ring fractures that intersected with graben faults on the earlier resurgent dome to produce the complex set of structures that localized the mid-Miocene epithermal gold veins. Later calc-alkaline monzonitic to quartz monzontic plutons solidified at 26.5-26.0 Ma as the underlying batholith rose through its volcanic cover. A new age from lavas near Uncompahgre Peak supports earlier interpretations that these lavas were fed by nearby 26 Ma monzonite intrusions. Nearly all of these intrusions are associated with subeconomic Mo and Cu mineralization and associated alteration, and new ages of 26.40 and 25.29 Ma from the Ute-Ulay and Lilly veins in the Lake City region show that some of the most important silver and base-metal veins were temporally and possibly genetically connected to these plutons. In addition, the Golden Fleece telluride vein cuts all of the post-Uncompahgre caldera volcanics in the area and is probably temporally related to this cycle, though its age of 27.5 ? 0.3 Ma was determined by less precise U/Pb methods. The 22.9 Ma Lake City caldera collapsed within the older Uncompahgre caldera structure but is petrologically unrelated to the older calc-alkaline activity. The distinctive suite of high-silica rhyolite tuff and alkaline resurgent intrusions indicates that it is closely related to the early stages of bimodal high-silica rhyolite-alkali basalt volcanism that accompanied the onset of extensional tectonism in the region. Both 40Ar/39Ar ages and paleomagnetic data confirm that the entire caldera sequence formed in less than 330,000 years. Only weak quartz vein mineralization is present in the center of the caldera, and it appears to be related to leaching of metals from the intracaldera tuffs above the resurgent intrusion. Massive alunitization and weak Mo and Cu mineralization along the eastern ring fracture are associated with calc-alkaline lavas and stocks related to late stages of the caldera cycle. These calc-alkaline stocks also appear to be genetically and temporally linked to a radial pattern of barite-precious metal veins on the northeastern margin of the Lake City caldera.

Geologic map of the Frisco quadrangle, Summit County, Colorado

USGS Publications Warehouse

Kellogg, Karl S.; Bartos, Paul J.; Williams, Cindy L.

2002-01-01

New 1:24,000-scale geologic mapping along the Interstate-70 urban corridor in western Colorado, in support of the USGS Central Region State/USGS Cooperative Geologic Mapping Project, is contributing to a more complete understanding of the stratigraphy, structure, tectonic evolution, and hazard potential of this rapidly developing region. The 1:24,000-scale Frisco quadrangle is near the headwaters of the Blue River and straddles features of the Blue River graben (Kellogg, K.S., 1999, Neogene basins of the northern Rio Grande rift?partitioning and asymmetry inherited from Laramide and older uplifts: Tectonophysics, v. 305, p. 141-152.), part of the northernmost reaches of the Rio Grande rift, a major late Oligocene to recent zone of extension that extends from Colorado to Mexico. The Williams Range thrust fault, the western structural margin of the Colorado Front Range, cuts the northeastern corner of the quadrangle. The oldest rocks in the quadrangle underlie the Tenmile Range and include biotite-sillimanite schist and gneiss, amphibolite, and migmatite that are intruded by granite inferred to be part of the 1,667-1,750 Ma Routt Plutonic Suite (Tweto, Ogden, 1987, Rock units of the Precambrian- basement in Colorado: U.S. Geological Survey Professional Paper 1321-A, 54 p.). The oldest sedimentary unit is the Pennsylvanian Maroon Formation, a sequence of red sandstone, conglomerate, and interbedded shale. The thickest sequence of sedimentary rocks is Cretaceous in age and includes at least 500 m of the Upper Cretaceous Pierre Shale. The sedimentary rocks are intruded by sills and dikes of dacite porphyry sills of Swan Mountain, dated at 44 Ma (Marvin, R.F., Mehnert, H.H., Naeser, C.W., and Zartman, R.E., 1989, U.S. Geological Survey radiometric ages, compilation ?C??Part five?Colorado, Montana, Utah, and Wyoming: Isochron/West, no. 53, p. 14-19. Simmons, E.C., and Hedge, C.E., 1978, Minor-element and Sr-isotope geochemistry of Tertiary stocks, Colorado mineral belt: Contributions to Mineralogy and Petrology, v. 67, p. 379-396.). Surficial deposits include (1) an old, deeply dissected landslide deposit, possibly as old as Tertiary, on the south flank of Tenderfoot Mountain, (2) deeply weathered, very coarse gravel deposits, mostly along Gold Run and underlying Mesa Cortina; the gravels are gold bearing and were mined by hydraulic methods in the 1800's, (3) glacial deposits of both Bull Lake (middle Pleistocene) and Pinedale (late Pleistocene) that were derived from large valley glaciers that flowed down Tenmile and North Tenmile Creeks; the town of Frisco is underlain mostly by Pinedale-age glacial outwash, (4) recent landslide deposits, including one large (about 1 square kilometer) area just downslope from Lilly Pad Lake, west of I-70, and (5)extensive colluvial and alluvial deposits. The latest seismic events appear to be middle Pliestocene in age and are associated with small scarps that cut Bull Lake till but do not cut Pinedale till.

Once-weekly dulaglutide versus once-daily liraglutide in metformin-treated patients with type 2 diabetes (AWARD-6): a randomised, open-label, phase 3, non-inferiority trial.

PubMed

Dungan, Kathleen M; Povedano, Santiago Tofé; Forst, Thomas; González, José G González; Atisso, Charles; Sealls, Whitney; Fahrbach, Jessie L

2014-10-11

Dulaglutide and liraglutide, both glucagon-like peptide-1 (GLP-1) receptor agonists, improve glycaemic control and reduce weight in patients with type 2 diabetes. In a head-to-head trial, we compared the safety and efficacy of once-weekly dulaglutide with that of once-daily liraglutide in metformin-treated patients with uncontrolled type 2 diabetes. We did a phase 3, randomised, open-label, parallel-group study at 62 sites in nine countries between June 20, 2012, and Nov 25, 2013. Patients with inadequately controlled type 2 diabetes receiving metformin (≥1500 mg/day), aged 18 years or older, with glycated haemoglobin (HbA1c) 7·0% or greater (≥53 mmol/mol) and 10·0% or lower (≤86 mmol/mol), and body-mass index 45 kg/m(2) or lower were randomly assigned to receive once-weekly dulaglutide (1·5 mg) or once-daily liraglutide (1·8 mg). Randomisation was done according to a computer-generated random sequence with an interactive voice response system. Participants and investigators were not masked to treatment allocation. The primary outcome was non-inferiority (margin 0·4%) of dulaglutide compared with liraglutide for change in HbA1c (least-squares mean change from baseline) at 26 weeks. Safety data were collected for a further 4 weeks' follow-up. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT01624259. We randomly assigned 599 patients to receive once-weekly dulaglutide (299 patients) or once-daily liraglutide (300 patients). 269 participants in each group completed treatment at week 26. Least-squares mean reduction in HbA1c was -1·42% (SE 0·05) in the dulaglutide group and -1·36% (0·05) in the liraglutide group. Mean treatment difference in HbA1c was -0·06% (95% CI -0·19 to 0·07, pnon-inferiority<0·0001) between the two groups. The most common gastrointestinal adverse events were nausea (61 [20%] in dulaglutide group vs 54 [18%] in liraglutide group), diarrhoea (36 [12%] vs 36 [12%]), dyspepsia (24 [8%] vs 18 [6%]), and vomiting (21 [7%] vs 25 [8%]), with similar rates of study or study drug discontinuation because of adverse events between the two groups (18 [6%] in each group). The hypoglycaemia rate was 0·34 (SE 1·44) and 0·52 (3·01) events per patient per year, respectively, and no severe hypoglycaemia was reported. Once-weekly dulaglutide is non-inferior to once-daily liraglutide for least-squares mean reduction in HbA1c, with a similar safety and tolerability profile. Eli Lilly and Company. Copyright © 2014 Elsevier Ltd. All rights reserved.

AMCP Partnership Forum: Advancing Value-Based Contracting.

PubMed

2017-11-01

During the past decade, payment models for the delivery of health care have undergone a dramatic shift from focusing on volume to focusing on value. This shift began with the Affordable Care Act and was reinforced by the Medicare Access and CHIP Reauthorization Act of 2015 (MACRA), which increased the emphasis on payment for delivery of quality care. Today, value-based care is a primary strategy for improving patient care while managing costs. This shift in payment models is expanding beyond the delivery of health care services to encompass models of compensation between payers and biopharmaceutical manufacturers. Value-based contracts (VBCs) have emerged as a mechanism that payers may use to better align their contracting structures with broader changes in the health care system. While pharmaceuticals represent a small share of total health care spending, it is one of the fastest-growing segments of the health care marketplace, and the increasing costs of pharmaceuticals necessitate more flexibility to contract in new ways based on the value of these products. Although not all products or services are appropriate for these types of contracts, VBCs could be a part of the solution to address increasing drug prices and overall drug spending. VBCs encompass a variety of different contracting strategies for biopharmaceutical products that do not base payment rates on volume. These contracts instead may include payment on the achievement of specific goals in a predetermined patient population and offer innovative solutions for quantifying and rewarding positive outcomes or otherwise reducing payer risk associated with pharmaceutical costs. To engage national stakeholders in a discussion of current practices, barriers, and potential benefits of VBCs, the Academy of Managed Care Pharmacy (AMCP) convened a Partnership Forum on Advancing Value-Based Contracting in Arlington, Virginia, on June 20-21, 2017. The goals of the VBC forum were as follows: (a) agree to a definition of a VBC for facilitating discussion with key policy makers and regulators; (b) determine strategies for advancing the development and utilization of performance benchmarks; (c) identify best practices in evaluating, implementing, and monitoring VBCs; and (d) develop action plans to mitigate legal and regulatory barriers to VBCs. More than 30 national and regional health care leaders representing health plans, integrated delivery systems, pharmacy benefit managers, employers, data and analytics companies, and biopharmaceutical companies participated. Speakers, panelists, and stakeholders attended the forum and explored the current environment for VBCs, identified challenges to the expansion of VBCs, offered potential solutions to those challenges, and developed an action plan for addressing selected challenges. The forum recommendations will be used by AMCP to establish a coalition of organizations to seek broader acceptance of VBCs in the marketplace and by policymakers. The recommendations will also help AMCP provide tools and resources to stakeholders in managing VBCs. This Partnership Forum was supported by Amgen, Bristol-Myers Squibb, Eli Lilly, Merck, the National Pharmaceutical Council, Novo Nordisk, Premier, the Pharmaceutical Research and Manufacturers of America, RxAnte, Takeda, and Xcenda.

Importance of Technical Writing in Engineering Education

NASA Astrophysics Data System (ADS)

Narayanan, M.

2010-12-01

It is important to recognize technical writing as a creative vehicle to communicate with the audience. It is indeed possible to motivate a reluctant learner by encouraging student writing combined with reading and research. John Kosakowski is of the opinion that writing assignments actually help to strengthen the self-confidence of a lethargic learner (Kosakowski, 1998). Researchers in the area of cognitive science and educational psychology are also of the opinion that encouraging students to writing actually helps the learners cultivate a positive attitude toward the subject matter in question. One must also recognize the fact that the students are indeed very reluctant to devote time and effort that requiress descriptive long writing assignments. One has to be more creative towards assignments that utilize problem-solving pedagogy (Saxe, 1988; Senge, 1990; Sims, 1995; Young & Young, 1999). Education World writer Gloria Chaika (Chaika, 2000) states that “Talent is important, but practice creates the solid base that allows that unique talent to soar. Like athletes, writers learn by doing. Good writing requires the same kind of dedicated practice that athletes put in. Young writers often lack the support they need to practice writing and develop their talent to the fullest, though.” Writing assignments have several key elements and the author has outlined below, some ideas for conducting assessment. 1. Identification of a purpose. 2. Focusing on the subject matter. 3. Attracting the attention of audience. 4. Format, flow and familiarity of the structure. 5. Observation of formality, voice and tone. 6. Promotion of critical thinking. 7. Importance of Logic and evidence-based reasoning. 8. Follows a realistic time line. 9. Process and procedure are properly outlined. References: Barr, R. B., & Tagg, J. (1995, November/December). From teaching to learning: A new paradigm for undergraduate education. Change: The Magazine of Higher Education, 13-24. Cox, M. D., Grasha, A., & Richlin, L. (1997, March). Town meeting. Between teaching model and learning model: Adapting and adopting bit by bit. Paper presented at the ninth annual Lilly Conference on College and University Teaching - West, Lake Arrowhead, CA. Narayanan, Mysore (2009). Assessment Based on the principles of Theodore Marchese. ASEE 116th Annual Conference and Exposition, Austin, TX. June 14-17, 2009. Paper # AC 2009-1532. Saxe, S. (1990, June). Peer influence and learning. Training and Development Journal, 42 (6), 50-53. Senge, P. M. (1990). The fifth discipline: The art and practice of the learning organization. New York: Currency Doubleday. Sims, R. R. (1992, Fall). Developing the learning climate in public sector training programs. Public Personnel Management, 21 (3), 335-346. Kosakowski, John, (1998). The Benefits of Information Technology. ERIC Digests; Technology Integration; Technology Role, ED0-IR-98-04 Chaika, Gloria (2000), Encourage Student Writing: Published on the Web, Education World http://www.education-world.com/a_tech/tech042.shtml

Writers, Athletes and Engineers Learn by Doing

NASA Astrophysics Data System (ADS)

Narayanan, M.

2009-12-01

The author strongly believes that when one provides students more opportunity to write and publish, one actually is helping those students learn better. Writing in reality reinforces the knowledge acquired and clarifies fuzzy, indistinct and indefinable points. In a Learning Paradigm or a Discovery Paradigm, it is observed that evaluation is holistic, and student success outcomes are those that are actually measured. Many scholars have recommended and supported a value-added concept of education by doing assessments before, during, and after a course (Barr & Tagg, 1995). Other scholars have argued that achievement of educational objectives is becoming less and less measurable whereas the need for accountability is rising to the surface more frequently. The literature supports our intuitive belief that education in a new learning paradigm will prepare students for the work ahead of them (Cox, Grasha, & Richlin 1997, March). Technical writing has been a part of engineering education for a long time. Regardless, it appears that engineering students are more interested in spending productive time learning the mathematical aspects of subject matter. The students are reluctant to devote time and effort that involves descriptive writing. The trend is to develop an interactive problem-solving pedagogy that encourages the development of learner’s creativity, understanding, written and oral communication skills (Saxe, 1988; Senge, 1990; Sims, 1995; Young & Young, 1999). It is essential for the students to recognize the fact that writing indeed enhances their grasp over technical content. The author has outlined seven areas for assessing a writing assignment. 1. The student writing has an identified a specific focus on a given purpose. 2. The author has indicated an audience for the writing assignment. 3. The writer has specified conventions for format, flow and structure. 4. The learner has documented conventions for formality, voice and tone. 5. The individual has provided evidence-based reasoning and critical thinking. 6. He/She has suggested a time-line for completing the assignment. 7. The person has completed the required process in the alloted time-line. In this presentation the author stresses the importance of writing assignments in engineering disciplines. References: Barr, R. B., & Tagg, J. (1995, November/December). From teaching to learning: A new paradigm for undergraduate education. Change: The Magazine of Higher Education, 13-24. Cox, M. D., Grasha, A., & Richlin, L. (1997, March). Town meeting. Between teaching model and learning model: Adapting and adopting bit by bit. Paper presented at the ninth annual Lilly Conference on College and University Teaching - West, Lake Arrowhead, CA. Narayanan, Mysore (2009). Assessment Based on the principles of Theodore Marchese. ASEE 116th Annual Conference and Exposition, Austin, TX. June 14-17, 2009. Paper # AC 2009-1532. Saxe, S. (1990, June). Peer influence and learning. Training and Development Journal, 42 (6), 50-53. Senge, P. M. (1990). The fifth discipline: The art and practice of the learning organization. New York: Currency Doubleday.

Seeing the unseen: Complete volcano deformation fields by recursive filtering of satellite radar interferograms

NASA Astrophysics Data System (ADS)

Gonzalez, Pablo J.

2017-04-01

Automatic interferometric processing of satellite radar data has emerged as a solution to the increasing amount of acquired SAR data. Automatic SAR and InSAR processing ranges from focusing raw echoes to the computation of displacement time series using large stacks of co-registered radar images. However, this type of interferometric processing approach demands the pre-described or adaptive selection of multiple processing parameters. One of the interferometric processing steps that much strongly influences the final results (displacement maps) is the interferometric phase filtering. There are a large number of phase filtering methods, however the "so-called" Goldstein filtering method is the most popular [Goldstein and Werner, 1998; Baran et al., 2003]. The Goldstein filter needs basically two parameters, the size of the window filter and a parameter to indicate the filter smoothing intensity. The modified Goldstein method removes the need to select the smoothing parameter based on the local interferometric coherence level, but still requires to specify the dimension of the filtering window. An optimal filtered phase quality usually requires careful selection of those parameters. Therefore, there is an strong need to develop automatic filtering methods to adapt for automatic processing, while maximizing filtered phase quality. Here, in this paper, I present a recursive adaptive phase filtering algorithm for accurate estimation of differential interferometric ground deformation and local coherence measurements. The proposed filter is based upon the modified Goldstein filter [Baran et al., 2003]. This filtering method improves the quality of the interferograms by performing a recursive iteration using variable (cascade) kernel sizes, and improving the coherence estimation by locally defringing the interferometric phase. The method has been tested using simulations and real cases relevant to the characteristics of the Sentinel-1 mission. Here, I present real examples from C-band interferograms showing strong and weak deformation gradients, with moderate baselines ( 100-200 m) and variable temporal baselines of 70 and 190 days over variable vegetated volcanoes (Mt. Etna, Hawaii and Nyragongo-Nyamulagira). The differential phase of those examples show intense localized volcano deformation and also vast areas of small differential phase variation. The proposed method outperforms the classical Goldstein and modified Goldstein filters by preserving subtle phase variations where the deformation fringe rate is high, and effectively suppressing phase noise in smoothly phase variation regions. Finally, this method also has the additional advantage of not requiring input parameters, except for the maximum filtering kernel size. References: Baran, I., Stewart, M.P., Kampes, B.M., Perski, Z., Lilly, P., (2003) A modification to the Goldstein radar interferogram filter. IEEE Transactions on Geoscience and Remote Sensing, vol. 41, No. 9., doi:10.1109/TGRS.2003.817212 Goldstein, R.M., Werner, C.L. (1998) Radar interferogram filtering for geophysical applications, Geophysical Research Letters, vol. 25, No. 21, 4035-4038, doi:10.1029/1998GL900033

Walter C. Williams

NASA Technical Reports Server (NTRS)

1949-01-01

Walter C. Williams arrived from the National Advisory Committee for Aeronautics, Langley Memorial Aeronautical Laboratory, Hampton, Virginia, on September 30, 1946, at the Muroc Army Air Field. He had been named the engineer-in-charge of the small group of five that came with him to the Rogers Dry Lakebed to take part in research flights of a joint NACA-Army Air Forces program involving the rocket-powered Bell XS-1. This established the first permanent National Advisory Committee for Aeronautics presence at the Mojave Desert site in California. This small group grew in numbers to 27 and received permanent status as the NACA Muroc Flight Test Unit from Hugh L. Dryden, NACA's Director of Research, on September 27, 1947. Walt was named Head of the Unit. On November 14, 1949, the Unit along with the 100 employees became the NACA High-Speed Flight Research Station with Walt Williams as Chief. Next came the move from the South Base site to the new headquarters, Bldg. 4800 on the north-west shore of the Rogers Dry lakebed on the Edwards Air Force Base complex. July 1, 1954 saw another name change to the NACA High-Speed Flight Station with Walt remaining the Chief to a complement of about 225 employees. Williams had received a Bachelor of Science Degree in aeronautical engineering from Louisiana State University, Baton Rouge, Louisiana, in 1939. After graduation, he was employed by the Glenn L. Martin Company of Baltimore, Maryland, and later that same year joined the staff of the NACA Langley Memorial Aeronautical Laboratory, where he worked as an engineer in the Flight Division. During the period from September 1946 to July 1954 Williams supervised the activities of several research projects. These included the first successful rocket-powered flight of the XS-1 made by Bell pilot Chalmers Goodlin on December 9, 1946; the record breaking flight of A.F. Captain Chuck Yeager on October 14, 1947, that exceeded the speed of sound; and the first flight of the jet-powered Douglas D-558-1 Skystreak by NACA pilot Howard C. Lilly on November 25, 1947. On March 10, 1948, Herbert Hoover was the first NACA pilot and the first civilian to fly supersonically (in the XS-1). Then came the testing of the tailless Northrop X-4 aircraft; the first flight of the variably swept wing Bell X-5 made by NACA pilot Joseph A. Walker; the first NACA flight of the Convair XF-92A, a delta wing configuration, on April 9, 1953; followed by the first Mach 2 flight on November 20, 1953, flown by NACA pilot Scott Crossfield in the rocket-powered Douglas D-558-2 Skyrocket. Walt continued to be in charge during the many name changes for the NACA-NASA organization, ending his stay as Chief of the National Aeronautics and Space Administration's Flight Research Center (todays NASA's Dryden Flight Research Center) in September 1959. See DIRECTORS, E-1364 for further information on Walter C. Williams.

Immune Protection against Lethal Fungal-Bacterial Intra-Abdominal Infections.

PubMed

Lilly, Elizabeth A; Ikeh, Melanie; Nash, Evelyn E; Fidel, Paul L; Noverr, Mairi C

2018-01-16

Polymicrobial intra-abdominal infections (IAIs) are clinically prevalent and cause significant morbidity and mortality, especially those involving fungi. Our laboratory developed a mouse model of IAI and demonstrated that intraperitoneal inoculation with Candida albicans or other virulent non- albicans Candida (NAC) species plus Staphylococcus aureus resulted in 70 to 80% mortality in 48 to 72 h due to robust local and systemic inflammation (sepsis). Surprisingly, inoculation with Candida dubliniensis or Candida glabrata with S. aureus resulted in minimal mortality, and rechallenge of these mice with lethal C. albicans / S. aureus (i.e., coninfection) resulted in >90% protection. The purpose of this study was to define requirements for C. dubliniensis / S. aureus -mediated protection and interrogate the mechanism of the protective response. Protection was conferred by C. dubliniensis alone or by killed C. dubliniensis plus live S. aureus S. aureus alone was not protective, and killed S. aureus compromised C. dubliniensis -induced protection. C. dubliniensis / S. aureus also protected against lethal challenge by NAC plus S. aureus and could protect for a long-term duration (60 days between primary challenge and C. albicans/S. aureus rechallenge). Unexpectedly, mice deficient in T and B cells (Rag-1 knockouts [KO]) survived both the initial C. dubliniensis/S. aureus challenge and the C. albicans/S. aureus rechallenge, indicating that adaptive immunity did not play a role. Similarly, mice depleted of macrophages prior to rechallenge were also protected. In contrast, protection was associated with high numbers of Gr-1 hi polymorphonuclear leukocytes (PMNLs) in peritoneal lavage fluid within 4 h of rechallenge, and in vivo depletion of Gr-1 + cells prior to rechallenge abrogated protection. These results suggest that Candida species can induce protection against a lethal C. albicans / S. aureus IAI that is mediated by PMNLs and postulated to be a unique form of trained innate immunity. IMPORTANCE Polymicrobial intra-abdominal infections are clinically devastating infections with high mortality rates, particularly those involving fungal pathogens, including Candida species. Even in patients receiving aggressive antimicrobial therapy, mortality rates remain unacceptably high. There are no available vaccines against IAI, which is complicated by the polymicrobial nature of the infection. IAI leads to lethal systemic inflammation (sepsis), which is difficult to target pharmacologically, as components of the inflammatory response are also needed to control the infection. Our studies demonstrate that prior inoculation with low-virulence Candida species provides strong protection against subsequent lethal infection with C. albicans and S. aureus Surprisingly, protection is long-lived but not mediated by adaptive (specific) immunity. Instead, protection is dependent on cells of the innate immune system (nonspecific immunity) and provides protection against other virulent Candida species. This discovery implies that a form of trained innate immunity may be clinically effective against polymicrobial IAI. Copyright © 2018 Lilly et al.

Ramucirumab versus placebo as second-line treatment in patients with advanced hepatocellular carcinoma following first-line therapy with sorafenib (REACH): a randomised, double-blind, multicentre, phase 3 trial.

PubMed

Zhu, Andrew X; Park, Joon Oh; Ryoo, Baek-Yeol; Yen, Chia-Jui; Poon, Ronnie; Pastorelli, Davide; Blanc, Jean-Frederic; Chung, Hyun Cheol; Baron, Ari D; Pfiffer, Tulio Eduardo Flesch; Okusaka, Takuji; Kubackova, Katerina; Trojan, Jorg; Sastre, Javier; Chau, Ian; Chang, Shao-Chun; Abada, Paolo B; Yang, Ling; Schwartz, Jonathan D; Kudo, Masatoshi

2015-07-01

VEGF and VEGF receptor-2-mediated angiogenesis contribute to hepatocellular carcinoma pathogenesis. Ramucirumab is a recombinant IgG1 monoclonal antibody and VEGF receptor-2 antagonist. We aimed to assess the safety and efficacy of ramucirumab in advanced hepatocellular carcinoma following first-line therapy with sorafenib. In this randomised, placebo-controlled, double-blind, multicentre, phase 3 trial (REACH), patients were enrolled from 154 centres in 27 countries. Eligible patients were aged 18 years or older, had hepatocellular carcinoma with Barcelona Clinic Liver Cancer stage C disease or stage B disease that was refractory or not amenable to locoregional therapy, had Child-Pugh A liver disease, an Eastern Cooperative Oncology Group performance status of 0 or 1, had previously received sorafenib (stopped because of progression or intolerance), and had adequate haematological and biochemical parameters. Patients were randomly assigned (1:1) to receive intravenous ramucirumab (8 mg/kg) or placebo every 2 weeks, plus best supportive care, until disease progression, unacceptable toxicity, or death. Randomisation was stratified by geographic region and cause of liver disease with a stratified permuted block method. Patients, medical staff, investigators, and the funder were masked to treatment assignment. The primary endpoint was overall survival in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01140347. Between Nov 4, 2010, and April 18, 2013, 565 patients were enrolled, of whom 283 were assigned to ramucirumab and 282 were assigned to placebo. Median overall survival for the ramucirumab group was 9·2 months (95% CI 8·0-10·6) versus 7·6 months (6·0-9·3) for the placebo group (HR 0·87 [95% CI 0·72-1·05]; p=0·14). Grade 3 or greater adverse events occurring in 5% or more of patients in either treatment group were ascites (13 [5%] of 277 patients treated with ramucirumab vs 11 [4%] of 276 patients treated with placebo), hypertension (34 [12%] vs ten [4%]), asthenia (14 [5%] vs five [2%]), malignant neoplasm progression (18 [6%] vs 11 [4%]), increased aspartate aminotransferase concentration (15 [5%] vs 23 [8%]), thrombocytopenia (13 [5%] vs one [<1%]), hyperbilirubinaemia (three [1%] vs 13 [5%]), and increased blood bilirubin (five [2%] vs 14 [5%]). The most frequently reported (≥1%) treatment-emergent serious adverse event of any grade or grade 3 or more was malignant neoplasm progression. Second-line treatment with ramucirumab did not significantly improve survival over placebo in patients with advanced hepatocellular carcinoma. No new safety signals were noted in eligible patients and the safety profile is manageable. Eli Lilly and Co. Copyright © 2015 Elsevier Ltd. All rights reserved.

Ramucirumab for Treating Advanced Gastric Cancer or Gastro-Oesophageal Junction Adenocarcinoma Previously Treated with Chemotherapy: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.

PubMed

Büyükkaramikli, Nasuh C; Blommestein, Hedwig M; Riemsma, Rob; Armstrong, Nigel; Clay, Fiona J; Ross, Janine; Worthy, Gill; Severens, Johan; Kleijnen, Jos; Al, Maiwenn J

2017-12-01

The National Institute for Health and Care Excellence (NICE) invited the company that manufactures ramucirumab (Cyramza ® , Eli Lilly and Company) to submit evidence of the clinical and cost effectiveness of the drug administered alone (monotherapy) or with paclitaxel (combination therapy) for treating adults with advanced gastric cancer or gastro-oesophageal junction (GC/GOJ) adenocarcinoma that were previously treated with chemotherapy, as part of the Institute's single technology appraisal (STA) process. Kleijnen Systematic Reviews Ltd (KSR), in collaboration with Erasmus University Rotterdam, was commissioned to act as the Evidence Review Group (ERG). This paper describes the company's submission, the ERG review, and NICE's subsequent decisions. Clinical effectiveness evidence for ramucirumab monotherapy (RAM), compared with best supportive care (BSC), was based on data from the REGARD trial. Clinical effectiveness evidence for ramucirumab combination therapy (RAM + PAC), compared with paclitaxel monotherapy (PAC), was based on data from the RAINBOW trial. In addition, the company undertook a network meta-analysis (NMA) to compare RAM + PAC with BSC and docetaxel. Cost-effectiveness evidence of monotherapy and combination therapy relied on partitioned survival, cost-utility models. The base-case incremental cost-effectiveness ratio (ICER) of the company was £188,640 (vs BSC) per quality-adjusted life-year (QALY) gained for monotherapy and £118,209 (vs BSC) per QALY gained for combination therapy. The ERG assessment indicated that the modelling structure represented the course of the disease; however, a few errors were identified and some of the input parameters were challenged. The ERG provided a new base case, with ICERs (vs BSC) of £188,100 (monotherapy) per QALY gained and £129,400 (combination therapy) per QALY gained and conducted additional exploratory analyses. The NICE Appraisal Committee (AC), considered the company's decision problem was in line with the NICE scope, with the exception of the choice of comparators for the combination therapy model. The most plausible ICER for ramucirumab monotherapy compared with BSC was £188,100 per QALY gained. The Committee considered that the ERG's exploratory analysis in which RAM + PAC was compared with PAC by using the direct head-to-head data (including utilities) from the RAINBOW trial, provided the most plausible ICER (i.e. £408,200 per QALY gained) for ramucirumab combination therapy. The Committee concluded that end-of-life considerations cannot be applied for either case, since neither failed to offer an extension to life of at least 3 months. The company did not submit a patient access scheme (PAS). After consideration of the evidence, the Committee concluded that ramucirumab alone or with paclitaxel could not be considered a cost-effective use of National Health Service resources for treating advanced GC/GOJ patients that were previously treated with chemotherapy, and therefore its use could not be recommended. We might wonder if a complete STA process is necessary for treatments without a PAS, which are, according to the company's submission, already associated with ICERs far above the currently accepted threshold in all (base-case, sensitivity and scenario) analyses.

Classroom Assessment Techniques

NASA Astrophysics Data System (ADS)

Narayanan, M.

2003-12-01

Provost David L. Potter of George Mason University chaired a joint task force and presented a report entitled ``Powerful Partnerships : A Shared Responsibility for Learnin'' in June 1998. The main goal is to make a difference in the quality of student learning. Further, it is important to assess this difference and document it. Clifford O. Young, Sr., & Laura Howzell Young of California State University, San Bernardino argue that a new paradigm for assessment, a learning paradigm, must be constructed to measure the success of new kinds of educational practices. Using two survey instruments, the Instruction Model Learning Model Questionnaire (IMLMQ) and the Student Evaluation of Teaching Effectiveness (SETE), they compared students' responses to the course when taught with traditional methods and with interactive methods. The results suggest that neither instrument effectively measures the kinds of learning promoted under the new paradigm. Linn, Baker, & Dunbar recommend that these newer assessment practices should be more authentic, that is, to involve students in the actual or simulated performance of a task or the documentation of the desired competency in a portfolio. Cerbin says that one of the most unfortunate consequences of a summative emphasis is that it inhibits open and productive discussions about teaching; in essence, it marginalizes the types of activity that could lead to better teaching (Cerbin, 1992). William Cerbin, who is the Director of the Center for Effective Teaching and learning, University Assessment Coordinator, and Professor of Psychology at the University of Wisconsin-LaCrosse is a recognized expert in the areas of cognition, language, and development. Edgerton, Hutchings, & Quinlan indicate that Teaching Portfolios may contain evidence of students' learning, but such information is optional, and when included, it may be only one of many pieces of material. Seldin, also supports this and stresses that the interplay between the instructor and the learner should be carefully observed and monitored. Forrest says that Student Portfolios, which document learning in more detail, seldom reveal how teaching contributes to students' progress. Cerbin further indicates that a course portfolio is essentially, a like a manuscript of scholarly work in progress. In this example, it is a work that explains what, how, and why students learn or do not learn in a course. In this paper, the author reports on a dozen techniques that could perhaps be used to document assessment of student learning. References : Cerbin, W. (1993). Fostering a culture of teaching as scholarship. The Teaching Professor, 7(3), 1-2. Edgerton, R., Hutchings, P., & Quinlan, P. (1991). The teaching portfolio: Capturing the scholarship in teaching. Washington, DC: American Association for Higher Education. Forrest, A. (1990). Time will tell: Portfolio-assisted assessment of general education. Washington, DC: American Association for Higher Education. Linn, R., Baker, E., & Dunbar, S. (1991). Complex, Performance-based Assessment: Expectations and Validation Criteria. Educational Researcher, 20 (8), 15-21. Narayanan, M. (2003). Assessment in Higher Education: Partnerships in Learning. Paper presented at the 23rd Annual Lilly Conference on College Teaching, Miami University, Oxford, OH. Seldin, P. (1991). The teaching portfolio. Bolton, MA: Anker. Young, C. O., Sr., & Young, L. H. (1999). Assessing Learning in Interactive Courses. Journal on Excellence in College Teaching, 10 (1), 63-76.

The Location and most Viable Magnetic Mineral of the Magnetic Layer of Mars Crust

NASA Astrophysics Data System (ADS)

Boutin, D.; Arkani-Hamed, J.

2010-12-01

The discovery of strong magnetic anomalies of remanant origin over the southern hemisphere of Mars [1] has provided the challenge to estimate the thickness of the magnetic crust and identify magnetic minerals capable of producing the anomalies. The power spectral analysis of the magnetic anomalies suggests a magnetic crust of 46 km thickness [2]. Estimates of depth to Curie temperature of viable magnetic mineral at about 4 Ga imply that the potentially magnetic layer must have been in the upper 70 km of the crust [3], and that the lower ~10 km must have been effectively demagnetized since by viscous decay [4]. The rock magnetic measurements show appreciable demagnetization at hydrostatic pressures up to 1.2 GPa [5], consistent with the above estimate of the magnetic layer thickness. The distinct lack of magnetic signature of many giant impact basins indicates that the impacts have demagnetized the crust. Detailed study of the magnetic anomalies surrounding Hellas, Isidis, and Argyre suggests that the area inside ~80% of the basin radius is almost completely demagnetized [6], as is confirmed by recent investigations [7,8]. First we use the evidence from these giant basins and show that Pierazzo et al. [1997] shock pressure distribution model with maximum decay exponent is most viable for Martian crust among the 6 models proposed. Using this model, we then determine the demagnetization of the crust by impacts that can create 10-500 km diameter craters. The surface of Mars is saturated by craters of diameters <100 km, which have completely demagnetized the upper ~10 km of Mars. The impacts that create 200-500 km diameter craters are capable of demagnetizing the entire crust beneath the craters. Second, we model topography, gravity, and magnetic data over all craters of diameters 300-600 km located in the southern hemisphere of Mars. The topography and gravity data suggest that majority of the craters are isostatically compensated and have distinct mantle plugs directly beneath, suggesting that impacts have effectively disturbed the crust. Many of the craters have well-defined magnetic signatures. Modeling a magnetic anomaly under the assumption that a) the mantle plug beneath a crater is non magnetic, b) the anomaly is due to impact demagnetization of the crust, and c) the impact heating has elevated the temperature and further enhanced viscous decay of magnetization in the lower part of the crust, provides a means to identify magnetite as the most viable magnetic carrier in the Martian crust. [1] Acuña, M.H. et al., Science 284, 790-793, 1999. [2] Voorhies, C.V. JGR, 821, 113, E04004, 2008. [3] Arkani-Hamed, J., JGR,110, 585, E08005, 2005. [4] Shahnas, H. and J. Arkani-Hamed, JGR, 112, E02009, 2007. [5] Bezaeva, N.S. et al., PEPI, 197, 7-20, 2010. [6] Mohit, P.S. and J. Arkani-Hamed, Icarus 168, 305-317, 2004. [7] Lillis, R.J.,et al., LPSC, XL, Abs. No. 1444, 2009. [8] Louzada, K.L., et al., EPSL, submitted, 2010. [9] Pierazzo, E. et al., Icarus 127, 408-423, 1997.

Necitumumab plus pemetrexed and cisplatin as first-line therapy in patients with stage IV non-squamous non-small-cell lung cancer (INSPIRE): an open-label, randomised, controlled phase 3 study.

PubMed

Paz-Ares, Luis; Mezger, Jörg; Ciuleanu, Tudor E; Fischer, Jürgen R; von Pawel, Joachim; Provencio, Mariano; Kazarnowicz, Andrzej; Losonczy, György; de Castro, Gilberto; Szczesna, Aleksandra; Crino, Lucio; Reck, Martin; Ramlau, Rodryg; Ulsperger, Ernst; Schumann, Christian; Miziara, Jose Elias A; Lessa, Álvaro E; Dediu, Mircea; Bálint, Beatrix; Depenbrock, Henrik; Soldatenkova, Victoria; Kurek, Raffael; Hirsch, Fred R; Thatcher, Nick; Socinski, Mark A

2015-03-01

Necitumumab is a second-generation recombinant human immunoglobulin G1 EGFR monoclonal antibody that competitively inhibits ligand binding. We aimed to compare necitumumab plus pemetrexed and cisplatin with pemetrexed and cisplatin alone in patients with previously untreated, stage IV, non-squamous non-small-cell lung cancer (NSCLC). We did this randomised, open-label, controlled phase 3 study at 103 sites in 20 countries. Patients aged 18 years or older, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 and adequate organ function, were randomly assigned 1:1 to treatment with a block randomisation scheme (block size of four) via a telephone-based interactive voice-response system or interactive web-response system. Patients received either cisplatin 75 mg/m(2) and pemetrexed 500 mg/m(2) on day 1 of a 3-week cycle for a maximum of six cycles alone, or with necitumumab 800 mg on days 1 and 8. Necitumumab was continued after the end of chemotherapy until disease progression or unacceptable toxic effects. Randomisation was stratified by smoking history, ECOG performance status, disease histology, and geographical region. Patients and study investigators were not masked to group assignment. The primary endpoint was overall survival. Efficacy analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00982111. Between Nov 11, 2009, and Feb 2, 2011, we randomly assigned 633 patients to receive either necitumumab plus pemetrexed and cisplatin (n=315) or pemetrexed and cisplatin alone (n=318). Enrolment was stopped on Feb 2, 2011, after a recommendation from the independent data monitoring committee. There was no significant difference in overall survival between treatment groups, with a median overall survival of 11·3 months (95% CI 9·5-13·4) in the necitumumab plus pemetrexed and cisplatin group versus 11·5 months (10·1-13·1) in the pemetrexed and cisplatin group (hazard ratio 1·01 [95% CI 0·84-1·21]; p=0·96). The incidence of grade 3 or worse adverse events, including deaths, was higher in the necitumumab plus pemetrexed and cisplatin group than in the pemetrexed and cisplatin group; in particular, deaths regarded as related to study drug were reported in 15 (5%) of 304 patients in the necitumumab group versus nine (3%) of 312 patients in the pemetrexed and cisplatin group. Serious adverse events were likewise more frequent in the necitumumab plus pemetrexed and cisplatin group than in the pemetrexed and cisplatin group (155 [51%] of 304 vs 127 [41%] of 312 patients). Patients in the necitumumab plus pemetrexed and cisplatin group had more grade 3-4 rash (45 [15%] of 304 vs one [<1%] of 312 patients in the pemetrexed and cisplatin alone group), hypomagnesaemia (23 [8%] vs seven [2%] patients), and grade 3 or higher venous thromboembolic events (23 [8%] vs 11 [4%] patients) than did those in the pemetrexed and cisplatin alone group. Our findings show no evidence to suggest that the addition of necitumumab to pemetrexed and cisplatin increases survival of previously untreated patients with stage IV non-squamous NSCLC. Unless future studies identify potentially useful predictive biomarkers, necitumumab is unlikely to provide benefit in this patient population when combined with pemetrexed and cisplatin. Eli Lilly and Company. Copyright © 2015 Elsevier Ltd. All rights reserved.

Disinformation squared: was the HIV-from-Fort-Detrick myth a Stasi success?

PubMed

Geissler, Erhard; Sprinkle, Robert Hunt

2013-01-01

When in May 1983 the acquired immunodeficiency syndrome (AIDS) was first securely attributed to a virus, eventually called the human immunodeficiency virus (HIV), many controversies arose. Among these was one centering on HIV's origin. A startling hypothesis, called here the "HIV-from-Fort-Detrick myth," asserted that HIV had been a product, accidental or intentional, of bioweaponry research. While its earliest identifiable contributors were in the West, this myth's most dynamic propagators were in the East. The Soviet security service, the KGB, took "active measures" to create and disseminate AIDS disinformation beginning no later than July 1983 and ending no earlier than October 1987. The East German security service, a complex bureaucracy popularly known as "the Stasi," was involved, too, but how early, how deeply, how uniformly, how ably, and how successfully has not been clear. Following German reunification, claims arose attributing to the Stasi the masterful execution of ingenious elements in a disinformation campaign they helped shape and soon came to dominate. We have tested these claims. Was the HIV-from-Fort-Detrick myth a Stasi success? Primary sources were documents and photographs assembled by the Ministry of State Security (MfS) of the German Democratic Republic (GDR or East Germany), the Ministry of Interior of the People's Republic of Bulgaria, and the United States Department of State; the estate of myth principals Jakob and Lilli Segal; the "AIDS box" in the estate of East German literary figure Stefan Heym; participant-observer recollections, interviews, and correspondence; and expert interviews. We examined secondary sources in light of primary sources. The HIV-from-Fort-Detrick myth had debuted in print in India in 1983 and had been described in publications worldwide prior to 1986, the earliest year for which we found any Stasi document mentioning the myth in any context. Many of the myth's exponents were seemingly independent conspiracy theorists. Its single most creative exponent was Jakob Segal, an idiosyncratic Soviet biologist long resident in, and long retired in, the GDR. Segal applied to the myth a thin but tenacious layer of plausibility. We could not exclude a direct KGB influence on him but found no evidence demonstrating it. The Stasi did not direct his efforts and had difficulty tracking his activities. The Stasi were prone to interpretive error and self-aggrandizement. They credited themselves with successes they did not achieve, and, in one instance, failed to appreciate that a major presumptive success had actually been a fiasco. Senior Stasi officers came to see the myth's propagation as an embarrassment threatening broader interests, especially the GDR's interest in being accepted as a scientifically sophisticated state. In 1986, 1988, and 1989, officers of HV A/X, the Stasi's disinformation and "active measures" department, discussed the myth in meetings with the Bulgarian secret service. In the last of these meetings, HV A/X officers tried to interest their Bulgarian counterparts in taking up, or taking over, the myth's propagation. Further efforts, if any, were obscured by collapse of the East German and Bulgarian governments. No, the HIV-from-Fort-Detrick myth was not a Stasi success. Impressions to the contrary can be attributed to reliance on presumptions, boasts, and inventions. Presumptions conceding to the Stasi an extraordinary operational efficiency and an irresistible competence - qualities we could not confirm in this case - made the boasts and inventions more convincing than their evidentiary basis, had it been known, would have allowed. The result was disinformation about disinformation, a product we call "disinformation squared."

Plant adaptive behaviour in hydrological models (Invited)

NASA Astrophysics Data System (ADS)

van der Ploeg, M. J.; Teuling, R.

2013-12-01

Models that will be able to cope with future precipitation and evaporation regimes need a solid base that describes the essence of the processes involved [1]. Micro-behaviour in the soil-vegetation-atmosphere system may have a large impact on patterns emerging at larger scales. A complicating factor in the micro-behaviour is the constant interaction between vegetation and geology in which water plays a key role. The resilience of the coupled vegetation-soil system critically depends on its sensitivity to environmental changes. As a result of environmental changes vegetation may wither and die, but such environmental changes may also trigger gene adaptation. Constant exposure to environmental stresses, biotic or abiotic, influences plant physiology, gene adaptations, and flexibility in gene adaptation [2-6]. Gene expression as a result of different environmental conditions may profoundly impact drought responses across the same plant species. Differences in response to an environmental stress, has consequences for the way species are currently being treated in models (single plant to global scale). In particular, model parameters that control root water uptake and plant transpiration are generally assumed to be a property of the plant functional type. Assigning plant functional types does not allow for local plant adaptation to be reflected in the model parameters, nor does it allow for correlations that might exist between root parameters and soil type. Models potentially provide a means to link root water uptake and transport to large scale processes (e.g. Rosnay and Polcher 1998, Feddes et al. 2001, Jung 2010), especially when powered with an integrated hydrological, ecological and physiological base. We explore the experimental evidence from natural vegetation to formulate possible alternative modeling concepts. [1] Seibert, J. 2000. Multi-criteria calibration of a conceptual runoff model using a genetic algorithm. Hydrology and Earth System Sciences 4(2): 215-224. [2] McClintock B. The significance of responses of the genome to challenge. Science 1984; 226: 792-801 [3] Ries G, Heller W, Puchta H, Sandermann H, Seldlitz HK, Hohn B. Elevated UV-B radiation reduces genome stability in plants. Nature 2000; 406: 98-101 [4] Lucht JM, Mauch-Mani B, Steiner H-Y, Metraux J-P, Ryals, J, Hohn B. Pathogen stress increases somatic recombination frequency in Arabidopsis. Nature Genet. 2002; 30: 311-314 [5] Kovalchuk I, Kovalchuk O, Kalck V., Boyko V, Filkowski J, Heinlein M, Hohn B. Pathogen-induced systemic plant signal triggers DNA rearrangements. Nature 2003; 423: 760-762 [6] Cullis C A. Mechanisms and control of rapid genomic changes in flax. Ann. Bot. (Lond.) 2005; 95: 201-206 [7] de Rosnay, P. and J. Polcher. 1998. Modelling root water uptake in a complex land surface scheme coupled to a GCM. Hydrology and Earth System Sciences 2: 239-255. [8] Feddes, R.A., H. Hoff, M. Bruen, T. Dawson, P. de Rosnay, P. Dirmeyer, R.B. Jackson, P. Kabat, A. Kleidon, A. Lilly, and A.J. Pitman. 2001. Modeling root water uptake in hydrological and climate models. Bulletin of the American Meteorological Society 82: 2797-2809. [9] Jung, M., M. Reichstein, P. Ciais, S.I. Seneviratne, J. Sheffield et al. 2010. Recent decline in the global land evaporation trend due to limited moisture supply. Nature 476: 951-954, doi:10.1038/nature09396.

Spectral Gap Energy Transfer in Atmospheric Boundary Layer

NASA Astrophysics Data System (ADS)

Bhushan, S.; Walters, K.; Barros, A. P.; Nogueira, M.

2012-12-01

Experimental measurements of atmospheric turbulence energy spectra show E(k) ~ k-3 slopes at synoptic scales (~ 600 km - 2000 km) and k-5/3 slopes at the mesoscales (< 400 km). The -5/3 spectra is presumably related to 3D turbulence which is dominated by the classical Kolmogrov energy cascade. The -3 spectra is related to 2D turbulence, which is dominated by strong forward scatter of enstrophy and weak forward scatter of energy. In classical 2D turbulence theory, it is expected that a strong backward energy cascade would develop at the synoptic scale, and that circulation would grow infinitely. To limit this backward transfer, energy arrest at macroscales must be introduced. The most commonly used turbulence models developed to mimic the above energy transfer include the energy backscatter model for 2D turbulence in the horizontal plane via Large Eddy Simulation (LES) models, dissipative URANS models in the vertical plane, and Ekman friction for the energy arrest. One of the controversial issues surrounding the atmospheric turbulence spectra is the explanation of the generation of the 2D and 3D spectra and transition between them, for energy injection at the synoptic scales. Lilly (1989) proposed that the existence of 2D and 3D spectra can only be explained by the presence of an additional energy injection in the meso-scale region. A second issue is related to the observations of dual peak spectra with small variance in meso-scale, suggesting that the energy transfer occurs across a spectral gap (Van Der Hoven, 1957). Several studies have confirmed the spectral gap for the meso-scale circulations, and have suggested that they are enhanced by smaller scale vertical convection rather than by the synoptic scales. Further, the widely accepted energy arrest mechanism by boundary layer friction is closely related to the spectral gap transfer. This study proposes an energy transfer mechanism for atmospheric turbulence with synoptic scale injection, wherein the generation of 2D and 3D spectra is explained using spectral gap energy transfer. The existence of the spectral gap energy transfer is validated by performing LES for the interaction of large scale circulation with a wall, and studying the evolution of the energy spectra both near to and far from the wall. Simulations are also performed using the Advanced Weather and Research Forecasting (WRF-ARW) for moist zonal flow over Gaussian ridge, and the energy spectra close and away from the ground are studied. The energy spectra predicted by WRF-ARW are qualitatively compared with LES results to emphasize the limitations of the currently used turbulence parameterizations. Ongoing validation efforts include: (1) extending the interaction of large scale circulation with wall simulations to finer grids to capture a wider range of wavenumbers; and (2) a coupled 2D-3D simulation is planned to predict the entire atmospheric turbulence spectra at a very low computational expense. The overarching objective of this study to develop turbulence modeling capability based on the energy transfer mechanisms proposed in this study. Such a model will be implemented in WRF-ARW, and applied to atmospheric simulations, for example the prediction of moisture convergence patterns at the meso-scale in the southeast United States (Tao & Barros, 2008).

Probability of major depression diagnostic classification using semi-structured versus fully structured diagnostic interviews.

PubMed

Levis, Brooke; Benedetti, Andrea; Riehm, Kira E; Saadat, Nazanin; Levis, Alexander W; Azar, Marleine; Rice, Danielle B; Chiovitti, Matthew J; Sanchez, Tatiana A; Cuijpers, Pim; Gilbody, Simon; Ioannidis, John P A; Kloda, Lorie A; McMillan, Dean; Patten, Scott B; Shrier, Ian; Steele, Russell J; Ziegelstein, Roy C; Akena, Dickens H; Arroll, Bruce; Ayalon, Liat; Baradaran, Hamid R; Baron, Murray; Beraldi, Anna; Bombardier, Charles H; Butterworth, Peter; Carter, Gregory; Chagas, Marcos H; Chan, Juliana C N; Cholera, Rushina; Chowdhary, Neerja; Clover, Kerrie; Conwell, Yeates; de Man-van Ginkel, Janneke M; Delgadillo, Jaime; Fann, Jesse R; Fischer, Felix H; Fischler, Benjamin; Fung, Daniel; Gelaye, Bizu; Goodyear-Smith, Felicity; Greeno, Catherine G; Hall, Brian J; Hambridge, John; Harrison, Patricia A; Hegerl, Ulrich; Hides, Leanne; Hobfoll, Stevan E; Hudson, Marie; Hyphantis, Thomas; Inagaki, Masatoshi; Ismail, Khalida; Jetté, Nathalie; Khamseh, Mohammad E; Kiely, Kim M; Lamers, Femke; Liu, Shen-Ing; Lotrakul, Manote; Loureiro, Sonia R; Löwe, Bernd; Marsh, Laura; McGuire, Anthony; Mohd Sidik, Sherina; Munhoz, Tiago N; Muramatsu, Kumiko; Osório, Flávia L; Patel, Vikram; Pence, Brian W; Persoons, Philippe; Picardi, Angelo; Rooney, Alasdair G; Santos, Iná S; Shaaban, Juwita; Sidebottom, Abbey; Simning, Adam; Stafford, Lesley; Sung, Sharon; Tan, Pei Lin Lynnette; Turner, Alyna; van der Feltz-Cornelis, Christina M; van Weert, Henk C; Vöhringer, Paul A; White, Jennifer; Whooley, Mary A; Winkley, Kirsty; Yamada, Mitsuhiko; Zhang, Yuying; Thombs, Brett D

2018-06-01

Different diagnostic interviews are used as reference standards for major depression classification in research. Semi-structured interviews involve clinical judgement, whereas fully structured interviews are completely scripted. The Mini International Neuropsychiatric Interview (MINI), a brief fully structured interview, is also sometimes used. It is not known whether interview method is associated with probability of major depression classification.AimsTo evaluate the association between interview method and odds of major depression classification, controlling for depressive symptom scores and participant characteristics. Data collected for an individual participant data meta-analysis of Patient Health Questionnaire-9 (PHQ-9) diagnostic accuracy were analysed and binomial generalised linear mixed models were fit. A total of 17 158 participants (2287 with major depression) from 57 primary studies were analysed. Among fully structured interviews, odds of major depression were higher for the MINI compared with the Composite International Diagnostic Interview (CIDI) (odds ratio (OR) = 2.10; 95% CI = 1.15-3.87). Compared with semi-structured interviews, fully structured interviews (MINI excluded) were non-significantly more likely to classify participants with low-level depressive symptoms (PHQ-9 scores ≤6) as having major depression (OR = 3.13; 95% CI = 0.98-10.00), similarly likely for moderate-level symptoms (PHQ-9 scores 7-15) (OR = 0.96; 95% CI = 0.56-1.66) and significantly less likely for high-level symptoms (PHQ-9 scores ≥16) (OR = 0.50; 95% CI = 0.26-0.97). The MINI may identify more people as depressed than the CIDI, and semi-structured and fully structured interviews may not be interchangeable methods, but these results should be replicated.Declaration of interestDrs Jetté and Patten declare that they received a grant, outside the submitted work, from the Hotchkiss Brain Institute, which was jointly funded by the Institute and Pfizer. Pfizer was the original sponsor of the development of the PHQ-9, which is now in the public domain. Dr Chan is a steering committee member or consultant of Astra Zeneca, Bayer, Lilly, MSD and Pfizer. She has received sponsorships and honorarium for giving lectures and providing consultancy and her affiliated institution has received research grants from these companies. Dr Hegerl declares that within the past 3 years, he was an advisory board member for Lundbeck, Servier and Otsuka Pharma; a consultant for Bayer Pharma; and a speaker for Medice Arzneimittel, Novartis, and Roche Pharma, all outside the submitted work. Dr Inagaki declares that he has received grants from Novartis Pharma, lecture fees from Pfizer, Mochida, Shionogi, Sumitomo Dainippon Pharma, Daiichi-Sankyo, Meiji Seika and Takeda, and royalties from Nippon Hyoron Sha, Nanzando, Seiwa Shoten, Igaku-shoin and Technomics, all outside of the submitted work. Dr Yamada reports personal fees from Meiji Seika Pharma Co., Ltd., MSD K.K., Asahi Kasei Pharma Corporation, Seishin Shobo, Seiwa Shoten Co., Ltd., Igaku-shoin Ltd., Chugai Igakusha and Sentan Igakusha, all outside the submitted work. All other authors declare no competing interests. No funder had any role in the design and conduct of the study; collection, management, analysis and interpretation of the data; preparation, review or approval of the manuscript; and decision to submit the manuscript for publication.

Prasugrel (Efient®) with percutaneous coronary intervention for treating acute coronary syndromes (review of TA182): systematic review and economic analysis.

PubMed

Greenhalgh, Janette; Bagust, Adrian; Boland, Angela; Dwan, Kerry; Beale, Sophie; Fleeman, Nigel; McEntee, Joanne; Dundar, Yenal; Richardson, Marty; Fisher, Michael

2015-04-01

Acute coronary syndromes (ACSs) are life-threatening conditions associated with acute myocardial ischaemia. There are three main types of ACS: ST segment elevation myocardial infarction (STEMI), non-ST segment elevation myocardial infarction (NSTEMI) and unstable angina (UA). One treatment for ACS is percutaneous coronary intervention (PCI) plus adjunctive treatment with antiplatelet drugs. Dual therapy antiplatelet treatment [aspirin plus either prasugrel (Efient(®), Daiichi Sankyo Company Ltd UK/Eli Lilly and Company Ltd), clopidogrel or ticagrelor (Brilique(®), AstraZeneca)] is standard in UK clinical practice. Prasugrel is the focus of this review. The remit is to appraise the clinical effectiveness and cost-effectiveness of prasugrel within its licensed indication for the treatment of ACS with PCI and is a review of National Institute for Health and Care Excellence technology appraisal TA182. Four electronic databases (MEDLINE, EMBASE, The Cochrane Library, PubMed) were searched from database inception to June 2013 for randomised controlled trials (RCTs) and to August 2013 for economic evaluations comparing prasugrel with clopidogrel or ticagrelor in ACS patients undergoing PCI. Clinical outcomes included non-fatal and fatal cardiovascular (CV) events, adverse effects of treatment and health-related quality of life (HRQoL). Cost-effectiveness outcomes included incremental cost per life-year gained and incremental cost per quality-adjusted life-year (QALY) gained. An independent economic model assessed four mutually exclusive subgroups: ACS patients treated with PCI for STEMI and with and without diabetes mellitus and ACS patients treated with PCI for UA or NSTEMI and with and without diabetes mellitus. No new RCTs were identified beyond that reported in TA182. TRITON-TIMI 38 (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel Thrombolysis in Myocardial Infarction 38) compared prasugrel with clopidogrel in ACS patients scheduled for PCI. No relevant economic evaluations were identified. Our analyses focused on a key subgroup of patients: those aged < 75 years who weighed > 60 kg (no previous stroke or transient ischaemic attack). For the primary composite end point (death from CV causes, non-fatal myocardial infarction or non-fatal stroke) statistically significantly fewer events occurred in the prasugrel arm (8.3%) than in the clopidogrel arm (11%). No statistically significant difference in major bleeding events was noted. However, there was a significant difference in favour of clopidogrel when major and minor bleeding events were combined (3.0 vs. 3.9%). No conclusions could be drawn regarding HRQoL. The results of sensitivity analyses confirmed that it is likely that, for all four ACS subgroups, within 5-10 years prasugrel is a cost-effective treatment option compared with clopidogrel at a willingness-to-pay threshold of £20,000 to £30,000 per QALY gained. At the full 40-year time horizon, all estimates are < £10,000 per QALY gained. Lack of data precluded a clinical comparison of prasugrel with ticagrelor; the comparative effectiveness of prasugrel compared with ticagrelor therefore remains unknown. The long-term modelling exercise is vulnerable to major assumptions about the continuation of early health outcome gains. A key strength of the review is that it demonstrates the cost-effectiveness of prasugrel compared with clopidogrel using the generic price of clopidogrel. Although the report demonstrates the cost-effectiveness of prasugrel compared with clopidogrel at a threshold of £20,000 to £30,000 per QALY gained, the long-term modelling is vulnerable to major assumptions regarding long-term gains. Lack of data precluded a clinical comparison of prasugrel with ticagrelor; the comparative effectiveness of prasugrel compared with ticagrelor therefore remains unknown. Well-audited data are needed from a long-term UK clinical registry on defined ACS patient groups treated with PCI who receive prasugrel, ticagrelor and clopidogrel. This study is registered as PROSPERO CRD42013005047. The National Institute for Health Research Health Technology Assessment programme.

Continuous glucose monitoring for patients with type 1 diabetes and impaired awareness of hypoglycaemia (IN CONTROL): a randomised, open-label, crossover trial.

PubMed

van Beers, Cornelis A J; DeVries, J Hans; Kleijer, Susanne J; Smits, Mark M; Geelhoed-Duijvestijn, Petronella H; Kramer, Mark H H; Diamant, Michaela; Snoek, Frank J; Serné, Erik H

2016-11-01

Patients with type 1 diabetes who have impaired awareness of hypoglycaemia have a three to six times increased risk of severe hypoglycaemia. We aimed to assess whether continuous glucose monitoring (CGM) improves glycaemia and prevents severe hypoglycaemia compared with self-monitoring of blood glucose (SMBG) in this high-risk population. We did a randomised, open-label, crossover trial (IN CONTROL) at two medical centres in the Netherlands. Eligible participants were patients diagnosed with type 1 diabetes according to American Diabetes Association criteria, aged 18-75 years, with impaired awareness of hypoglycaemia as confirmed by a Gold score of at least 4, and treated with either continuous subcutaneous insulin infusion or multiple daily insulin injections and doing at least three SMBG measurements per day. After screening, re-education about diabetes management, and a 6-week run-in phase (to obtain baseline CGM data), we randomly assigned patients (1:1) with a computer-generated allocation sequence (block size of four) to either 16 weeks of CGM followed by 12 weeks of washout and 16 weeks of SMBG, or 16 weeks of SMBG followed by 12 weeks of washout and 16 weeks of CGM (where the SMBG phase was the control). During the CGM phase, patients used a real-time CGM system consisting of a Paradigm Veo system with a MiniLink transmitter and an Enlite glucose sensor (Medtronic, CA, USA). During the SMBG phase, patients were equipped with a masked CGM device, consisting of an iPro 2 continuous glucose monitor and an Enlite glucose sensor, which does not display real-time glucose values. The number of SMBG measurements per day and SMBG systems were not standardised between patients, to mimic real-life conditions. During both intervention periods, patients attended follow-up visits at the centres each month and had telephone consultations 2 weeks after each visit inquiring about adverse events, episodes of hypoglycaemia, etc. The primary endpoint was the mean difference in percentage of time spent in normoglycaemia (4-10 mmol/L) over the total intervention periods, analysed on an intention-to-treat basis. Severe hypoglycaemia (requiring third party assistance) was a secondary endpoint. This trial is registered with ClinicalTrials.gov, number NCT01787903. Between March 4, 2013, and Feb 9, 2015, we recruited and randomly assigned 52 patients to either the CGM-SMBG sequence (n=26) or the SMBG-CGM sequence (n=26). The last patient visit was on March 21, 2016. Time spent in normoglycaemia was higher during CGM than during SMBG: 65·0% (95% CI 62·8-67·3) versus 55·4% (53·1-57·7; mean difference 9·6%, 95% CI 8·0-11·2; p<0·0001), with reductions in both time spent in hypoglycaemia (ie, blood glucose ≤3·9 mmol/L [6·8% vs 11·4%, mean difference 4·7%, 3·4-5·9; p<0·0001]) and time spent in hyperglycaemia (ie, blood glucose >10 mmol/L [28·2% vs 33·2%, mean difference 5·0%, 3·1-6·9; p<0·0001]). During CGM, the number of severe hypoglycaemic events was lower (14 events vs 34 events, p=0·033). Five serious adverse events other than severe hypoglycaemia occurred during the trial, but all were deemed unrelated to the trial intervention. Additionally, no mild to moderate adverse events were related to the trial intervention. CGM increased time spent in normoglycaemia and reduced severe hypoglycaemia in patients with type 1 diabetes and impaired awareness of hypoglycaemia, compared with SMBG. Our results support the concept of using CGM in this high-risk population. Eli Lilly and Sanofi. Copyright © 2016 Elsevier Ltd. All rights reserved.

Eocene Total Petroleum System -- North and East of the Eocene West Side Fold Belt Assessment Unit of the San Joaquin Basin Province: Chapter 19 in Petroleum systems and geologic assessment of oil and gas in the San Joaquin Basin Province, California

USGS Publications Warehouse

Gautier, Donald L.; Hosford Scheirer, Allegra

2009-01-01

The North and East of Eocene West Side Fold Belt Assessment Unit (AU) of the Eocene Total Petroleum System of the San Joaquin Basin Province comprises all hydrocarbon accumulations within the geographic and stratigraphic limits of this confirmed AU. Oil and associated gas accumulations occur in Paleocene through early middle Miocene marine to nonmarine sandstones found on the comparatively stable northeast shelf of the basin. The assessment unit is located north and east of the thickest accumulation of Neogene sediments and the west side fold belt. The area enclosed by the AU has been affected by only mild deformation since Eocene time. Traps containing known accumulations are mostly low-relief domes, anticlines, and up-dip basin margin traps with faulting and stratigraphic components. Map boundaries of the assessment unit are shown in figures 19.1 and 19.2; this assessment unit replaces the Northeast Shelf of Neogene Basin play 1006, the East Central Basin and Slope North of Bakersfield Arch play 1010, and part of the West Side Fold Belt Sourced by Pre-middle Miocene Rocks play 1005 considered by the U.S. Geological Survey (USGS) in their 1995 National Assessment (Beyer, 1996). Stratigraphically, the AU includes rocks from the uppermost crystalline basement to the topographic surface. In the region of overlap with the Central Basin Monterey Diagenetic Traps Assessment Unit, the North and East of Eocene West Side Fold Belt AU extends from basement rocks to the top of the Temblor Formation (figs. 19.3 and 19.4). In map view, the northern boundary of the assessment unit corresponds to the northernmost extent of Eocene-age Kreyenhagen Formation. The northeast boundary is the eastern limit of possible oil reservoir rocks near the eastern edge of the basin. The southeast boundary corresponds to the pinch-out of Stevens sand of Eckis (1940) to the south, which approximately coincides with the northern flank of the Bakersfield Arch (fig. 19.1). The AU is bounded on the southwest by the limit of major west side structural deformation and to the northwest by the San Andreas Fault and the limit of hydrocarbon-prospective strata in the Coast Ranges. As described by Gautier and others (this volume, chapter 2), existing oil fields in the San Joaquin Basin Province were assigned to assessment units based on the identified petroleum system and reservoir rocks in each field. Vallecitos oil field in the extreme northwest corner of the basin was assigned to the Eocene Total Petroleum System, because oil analyses conducted for this San Joaquin Basin assessment indicate that Eocene oil charged the reservoir rocks (Lillis and Magoon, this volume, chapter 9). Some literature classifies the Vallecitos oil field as part of the northernmost fold of the basin’s west side fold belt (see, for example, Rentschler, 1985; Bartow, 1991), but because of the oil field’s spatial separation and differing trend from the west side fold belt, Vallecitos field was considered here to be within the North and East of Eocene West Side Fold Belt Assessment Unit rather than in the other assessment unit in the Eocene Total Petroleum System, the Eocene West Side Fold Belt. Primary fields in the assessment unit are defined as those containing hydrocarbon resources greater than the USGS minimum threshold for assessment (0.5 million barrels of oil); secondary fields contain smaller volumes of oil but constitute a significant show of hydrocarbons.

Necitumumab plus gemcitabine and cisplatin versus gemcitabine and cisplatin alone as first-line therapy in patients with stage IV squamous non-small-cell lung cancer (SQUIRE): an open-label, randomised, controlled phase 3 trial.

PubMed

Thatcher, Nick; Hirsch, Fred R; Luft, Alexander V; Szczesna, Aleksandra; Ciuleanu, Tudor E; Dediu, Mircea; Ramlau, Rodryg; Galiulin, Rinat K; Bálint, Beatrix; Losonczy, György; Kazarnowicz, Andrzej; Park, Keunchil; Schumann, Christian; Reck, Martin; Depenbrock, Henrik; Nanda, Shivani; Kruljac-Letunic, Anamarija; Kurek, Raffael; Paz-Ares, Luis; Socinski, Mark A

2015-07-01

Necitumumab is a second-generation, recombinant, human immunoglobulin G1 EGFR antibody. In this study, we aimed to compare treatment with necitumumab plus gemcitabine and cisplatin versus gemcitabine and cisplatin alone in patients with previously untreated stage IV squamous non-small-cell lung cancer. We did this open-label, randomised phase 3 study at 184 investigative sites in 26 countries. Patients aged 18 years or older with histologically or cytologically confirmed stage IV squamous non-small-cell lung cancer, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 and adequate organ function and who had not received previous chemotherapy for their disease were eligible for inclusion. Enrolled patients were randomly assigned centrally 1:1 to a maximum of six 3-week cycles of gemcitabine and cisplastin chemotherapy with or without necitumumab according to a block randomisation scheme (block size of four) by a telephone-based interactive voice response system or interactive web response system. Chemotherapy was gemcitabine 1250 mg/m(2) administered intravenously over 30 min on days 1 and 8 of a 3-week cycle and cisplatin 75 mg/m(2) administered intravenously over 120 min on day 1 of a 3-week cycle. Necitumumab 800 mg, administered intravenously over a minimum of 50 min on days 1 and 8, was continued after the end of chemotherapy until disease progression or intolerable toxic side-effects occurred. Randomisation was stratified by ECOG performance status and geographical region. Neither physicians nor patients were masked to group assignment because of the expected occurrence of acne-like rash--a class effect of EGFR antibodies--that would have unmasked most patients and investigators to treatment. The primary endpoint was overall survival, analysed by intention to treat. We report the final clinical analysis. This study is registered with ClinicalTrials.gov, number NCT00981058. Between Jan 7, 2010, and Feb 22, 2012, we enrolled 1093 patients and randomly assigned them to receive necitumumab plus gemcitabine and cisplatin (n=545) or gemcitabine and cisplatin (n=548). Overall survival was significantly longer in the necitumumab plus gemcitabine and cisplatin group than in the gemcitabine and cisplatin alone group (median 11·5 months [95% CI 10·4-12·6]) vs 9·9 months [8·9-11·1]; stratified hazard ratio 0·84 [95% CI 0·74-0·96; p=0·01]). In the necitumumab plus gemcitabine and cisplatin group, the number of patients with at least one grade 3 or worse adverse event was higher (388 [72%] of 538 patients) than in the gemcitabine and cisplatin group (333 [62%] of 541), as was the incidence of serious adverse events (257 [48%] of 538 patients vs 203 [38%] of 541). More patients in the necitumumab plus gemcitabine and cisplatin group had grade 3-4 hypomagnesaemia (47 [9%] of 538 patients in the necitumumab plus gemcitabine and cisplatin group vs six [1%] of 541 in the gemcitabine and cisplatin group) and grade 3 rash (20 [4%] vs one [<1%]). Including events related to disease progression, adverse events with an outcome of death were reported for 66 (12%) of 538 patients in the necitumumab plus gemcitabine and cisplatin group and 57 (11%) of 541 patients in the gemcitabine and cisplatin group; these were deemed to be related to study drugs in 15 (3%) and ten (2%) patients, respectively. Overall, we found that the safety profile of necitumumab plus gemcitabine and cisplatin was acceptable and in line with expectations. Our findings show that the addition of necitumumab to gemcitabine and cisplatin chemotherapy improves overall survival in patients with advanced squamous non-small-cell lung cancer and represents a new first-line treatment option for this disease. Eli Lilly and Company. Copyright © 2015 Elsevier Ltd. All rights reserved.

Topotecan, pegylated liposomal doxorubicin hydrochloride, paclitaxel, trabectedin and gemcitabine for advanced recurrent or refractory ovarian cancer: a systematic review and economic evaluation.

PubMed

Edwards, Steven J; Barton, Samantha; Thurgar, Elizabeth; Trevor, Nicola

2015-01-01

Ovarian cancer is the fifth most common cancer in the UK, and the fourth most common cause of cancer death. Of those people successfully treated with first-line chemotherapy, 55-75% will relapse within 2 years. At this time, it is uncertain which chemotherapy regimen is more clinically effective and cost-effective for the treatment of recurrent, advanced ovarian cancer. To determine the comparative clinical effectiveness and cost-effectiveness of topotecan (Hycamtin(®), GlaxoSmithKline), pegylated liposomal doxorubicin hydrochloride (PLDH; Caelyx(®), Schering-Plough), paclitaxel (Taxol(®), Bristol-Myers Squibb), trabectedin (Yondelis(®), PharmaMar) and gemcitabine (Gemzar(®), Eli Lilly and Company) for the treatment of advanced, recurrent ovarian cancer. Electronic databases (MEDLINE(®), EMBASE, Cochrane Central Register of Controlled Trials, Health Technology Assessment database, NHS Economic Evaluations Database) and trial registries were searched, and company submissions were reviewed. Databases were searched from inception to May 2013. A systematic review of the clinical and economic literature was carried out following standard methodological principles. Double-blind, randomised, placebo-controlled trials, evaluating topotecan, PLDH, paclitaxel, trabectedin and gemcitabine, and economic evaluations were included. A network meta-analysis (NMA) was carried out. A de novo economic model was developed. For most outcomes measuring clinical response, two networks were constructed: one evaluating platinum-based regimens and one evaluating non-platinum-based regimens. In people with platinum-sensitive disease, NMA found statistically significant benefits for PLDH plus platinum, and paclitaxel plus platinum for overall survival (OS) compared with platinum monotherapy. PLDH plus platinum significantly prolonged progression-free survival (PFS) compared with paclitaxel plus platinum. Of the non-platinum-based treatments, PLDH monotherapy and trabectedin plus PLDH were found to significantly increase OS, but not PFS, compared with topotecan monotherapy. In people with platinum-resistant/-refractory (PRR) disease, NMA found no statistically significant differences for any treatment compared with alternative regimens in OS and PFS. Economic modelling indicated that, for people with platinum-sensitive disease and receiving platinum-based therapy, the estimated probabilistic incremental cost-effectiveness ratio [ICER; incremental cost per additional quality-adjusted life-year (QALY)] for paclitaxel plus platinum compared with platinum was £24,539. Gemcitabine plus carboplatin was extendedly dominated, and PLDH plus platinum was strictly dominated. For people with platinum-sensitive disease and receiving non-platinum-based therapy, the probabilistic ICERs associated with PLDH compared with paclitaxel, and trabectedin plus PLDH compared with PLDH, were estimated to be £25,931 and £81,353, respectively. Topotecan was strictly dominated. For people with PRR disease, the probabilistic ICER associated with topotecan compared with PLDH was estimated to be £324,188. Paclitaxel was strictly dominated. As platinum- and non-platinum-based treatments were evaluated separately, the comparative clinical effectiveness and cost-effectiveness of these regimens is uncertain in patients with platinum-sensitive disease. For platinum-sensitive disease, it was not possible to compare the clinical effectiveness and cost-effectiveness of platinum-based therapies with non-platinum-based therapies. For people with platinum-sensitive disease and treated with platinum-based therapies, paclitaxel plus platinum could be considered cost-effective compared with platinum at a threshold of £30,000 per additional QALY. For people with platinum-sensitive disease and treated with non-platinum-based therapies, it is unclear whether PLDH would be considered cost-effective compared with paclitaxel at a threshold of £30,000 per additional QALY; trabectedin plus PLDH is unlikely to be considered cost-effective compared with PLDH. For patients with PRR disease, it is unlikely that topotecan would be considered cost-effective compared with PLDH. Randomised controlled trials comparing platinum with non-platinum-based treatments might help to verify the comparative effectiveness of these regimens. This study is registered as PROSPERO CRD42013003555. The National Institute for Health Research Health Technology Assessment programme.

Myostatin antibody (LY2495655) in older weak fallers: a proof-of-concept, randomised, phase 2 trial.

PubMed

Becker, Clemens; Lord, Stephen R; Studenski, Stephanie A; Warden, Stuart J; Fielding, Roger A; Recknor, Christopher P; Hochberg, Marc C; Ferrari, Serge L; Blain, Hubert; Binder, Ellen F; Rolland, Yves; Poiraudeau, Serge; Benson, Charles T; Myers, Stephen L; Hu, Leijun; Ahmad, Qasim I; Pacuch, Kelli R; Gomez, Elisa V; Benichou, Olivier

2015-12-01

Myostatin inhibits skeletal muscle growth. The humanised monoclonal antibody LY2495655 (LY) binds and neutralises myostatin. We aimed to test whether LY increases appendicular lean body mass (aLBM) and improves physical performance in older individuals who have had recent falls and low muscle strength and power. In this proof-of-concept, randomised, placebo-controlled, double-blind, parallel, multicentre, phase 2 study, we recruited patients aged 75 years or older who had fallen in the past year from 21 investigator sites across Argentina, Australia, France, Germany, Sweden, and the USA. Eligible patients had low performance on hand grip strength and chair rise tests, tested with the procedure described by Guralnik and colleagues. Participants were stratified by country, age, hand grip strength, and performance on the chair rise test, and were randomly assigned (1:1) by a computer-generated random sequence to receive subcutaneous injections of placebo or 315 mg LY at weeks 0 (randomisation visit), 4, 8, 12, 16, and 20, followed by 16 weeks observation. The primary outcome was change in aLBM from baseline to 24 weeks. We measured physical performance as secondary outcomes (four-step stair climbing time, usual gait speed, and time to rise five times from a chair without arms, or with arms for participants unable to do it without arms) and exploratory outcomes (12-step stair climbing test, 6-min walking distance, fast gait speed, hand grip strength, and isometric leg extension strength). Efficacy analyses included all randomly assigned patients who received at least one dose and had a baseline and at least one subsequent measure. The primary analysis and all other tests of treatment effect (except physical performance tests) were done at a two-sided alpha level of 0·05. Tests of treatment effect on physical performance tests were done at a pre-specified two-sided alpha level of 0·1. This trial is registered with ClinicalTrials.gov, number NCT01604408. Between June 19, 2012, and Dec 12, 2013, we screened 365 patients. 99 were randomly assigned to receive placebo and 102 to receive LY. Treatment was completed in 85 (86%) of patients given placebo and in 82 (80%) given LY. At 24 weeks, the least-squares mean change in aLBM was -0·123 kg (95% CI -0·287 to 0·040) in the placebo group and 0·303 kg (0·135 to 0·470) in the LY group, a difference of 0·43 kg (95% CI 0·192 to 0·660; p<0·0001). Stair climbing time (four-step and 12-step tests), chair rise with arms, and fast gait speed improved significantly from baseline to week 24 with differences between LY and placebo of respectively -0·46 s (p=0·093), -1·28 s (p=0·011), -4·15 s (p=0·054), and 0·05 m/s (p=0·088). No effect was detected for other performance-based measures. Injection site reactions were recorded in nine (9%) patients given placebo and in 31 (30%) patients given LY (p<0·0001), and were generally mild, and led to treatment discontinuation in two patients given LY. Our findings show LY treatment increases lean mass and might improve functional measures of muscle power. Although additional studies are needed to confirm these results, our data suggest LY should be tested for its potential ability to reduce the risk of falls or physical dependency in older weak fallers. Eli Lilly and Company. Copyright © 2015 Elsevier Ltd. All rights reserved.

Economic Impact of Above-Label Dosing with Etanercept, Adalimumab, or Ustekinumab in Patients with Psoriasis.

PubMed

Feldman, Steven R; Zhao, Yang; Zhou, Huanxue; Herrera, Vivian; Tian, Haijun; Li, Yunfeng

2017-05-01

Patients with moderate-to-severe psoriasis may be treated with above-label doses of biologics in an attempt to optimize outcomes. Dose escalation will have an effect on the cost of treatment. To examine costs related to above-label use of etanercept, adalimumab, and ustekinumab among patients with moderate-to-severe psoriasis. A retrospective study was performed using a large U.S. claims database. Patients were included in the study if they were aged ≥ 18 years with a diagnosis of psoriasis (excluding psoriatic arthritis) and had at least 1 medication fill for etanercept, adalimumab, or ustekinumab between January 1, 2011, and June 30, 2012. In addition, patients were required to have continuous enrollment for 12 months before, and 18 months after, the first biologic use (index biologic) during the maintenance period (defined as the period following the induction period in which each agent was titrated to its recommended maintenance dose per label) and at least 1 prescription filled for the index biologic during the 18 months after the maintenance period. Extensive above-label use was defined as taking an above-label dose (at least 10% higher than indicated in the label) for ≥ 180 days over a 12-month period following the maintenance period. Percentages of patients with extensive above-label use, mean number of days of above-label use, and additional costs associated with extensive above-label use (abovelabel cost minus on-label cost) were examined. The study included 3,310 patients who started treatment with etanercept (n = 1,443), adalimumab (n = 1,447), or ustekinumab (n = 420). Extensive above-label use occurred in 20.0% of etanercept patients, 2.6% of adalimumab patients, and 14.8% of ustekinumab patients. The mean duration of extensive above-label use was roughly similar for the 3 biologics (mean days [±SD]: 282 [±55] for etanercept, 279 [±57] for adalimumab, and 305 [±43] for ustekinumab). Additional annual costs per patient because of extensive above-label use were $19,458 for etanercept, $18,972 for adalimumab, and $21,045 for ustekinumab. Total additional annual costs were $5,623,362 for etanercept, $701,964 for adalimumab, and $1,304,790 for ustekinumab. Psoriasis patients treated with etanercept, adalimumab, or ustekinumab had extensive above-label use over the 12-month follow-up period, which subsequently led to higher costs. Novartis Pharmaceuticals Corporation sponsored this study and the resultant publication. BioScience Communications provided medical writing and editorial support, which was also funded by Novartis Pharmaceuticals Corporation. Feldman was engaged by Novartis Pharmaceuticals as a paid clinical expert and scientific advisor for this study. He has received research support and speaking and/or consulting fees from AbbVie, Advance Medical, Amgen, Anacor, Astellas, Baxter, Boehringer Ingelheim, Caremark, Celgene, Eli Lilly, Galderma, GSK/Stiefel, Informa, Janssen, LEO Pharma, Merck, Merz, Mylan, National Biological, National Psoriasis Foundation, Pfizer, Qurient, Suncare Research, UpToDate, and Valeant; is the founder and majority owner of www.DrScore.com ; and is founder and part owner of Causa Research. Zhao, Herrera, Tian, and Li are employees of Novartis Pharmaceuticals. Zhou is a paid consultant for Novartis Pharmaceuticals and is an employee of KMK Consulting. Study concept and design were contributed by Feldman, Zhao, Herrera, and Li. Zhou and Li were responsible for data collection. Data were interpreted by Feldman and Zhao, with assistance from Zhou, Herrera, Tian, and Li. The manuscript was written primarily by Feldman and Zhao, with assistance from Zhou and Li. The manuscript was revised by Feldman and Zhao, assisted by Zhou, Herrera, Tian, and Li. Portions of this work were presented at the 34th Anniversary Fall Clinical Dermatology Conference in Las Vegas, Nevada, October 1-4, 2015.

Optimizing Anti-VEGF Treatment Outcomes for Patients with Neovascular Age-Related Macular Degeneration.

PubMed

Wykoff, Charles C; Clark, W Lloyd; Nielsen, Jared S; Brill, Joel V; Greene, Laurence S; Heggen, Cherilyn L

2018-02-01

The introduction of anti-vascular endothelial growth factor (anti-VEGF) drugs to ophthalmology has revolutionized the treatment of neovascular age-related macular degeneration (nAMD). Despite this significant progress, gaps and challenges persist in the diagnosis of nAMD, initiation of treatment, and management of frequent intravitreal injections. Thus, nAMD remains a leading cause of blindness in the United States. To present current knowledge, evidence, and expert perspectives on anti-VEGF therapies in nAMD to support managed care professionals and providers in decision making and collaborative strategies to overcome barriers to optimize anti-VEGF treatment outcomes among nAMD patients. Three anti-VEGF therapies currently form the mainstay of treatment for nAMD, including 2 therapies approved by the FDA for treatment of nAMD (aflibercept and ranibizumab) and 1 therapy approved by the FDA for oncology indications and used off-label for treatment of nAMD (bevacizumab). In clinical trials, each of the 3 agents maintained visual acuity (VA) in approximately 90% or more of nAMD patients over 2 years. However, in long-term and real-world settings, significant gaps and challenges in diagnosis, treatment, and management pose barriers to achieving optimal outcomes for patients with nAMD. Many considerations, including individual patient characteristics, on-label versus off-label treatment, repackaging, and financial considerations, add to the complexity of nAMD decision making and management. Many factors may contribute to additional challenges leading to suboptimal long-term outcomes among nAMD patients, such as delays in diagnosis and/or treatment approval and initiation, individual patient response to different anti-VEGF therapies, lapses in physician regimentation of anti-VEGF injection and monitoring, and inadequate patient adherence to treatment and monitoring. These latter factors highlight the considerable logistical, emotional, and financial burdens of long-term, frequent intravitreal injections and the vital importance of personalized approaches to anti-VEGF treatment decision making and management for patients with nAMD. To address these challenges and reduce the number of yearly injections, studies have examined alternative dosing regimens, including extended fixed intervals, as needed, and treat-and-extend strategies in specific nAMD patient populations. New clinical evidence and insights into expert clinical practice discussed in this article can support managed care professionals in the key role they play in addressing challenges in nAMD treatment and management and optimizing patient outcomes through appropriate management of anti-VEGF treatment. PRIME Education is an independent medical education company and has been an accredited provider of continuing education for 23 years. There is no fee for this activity as it is sponsored by PRIME through an educational grant from Regeneron. All authors contributed to the writing and reviewing of the article. Wykoff reports consultancies/research grants from Alcon Laboratories, Genentech/Roche, Clearside, and Iconic Therapeutics; consultancies/honoraria, research grants, and speaker fees from Allergan and Regeneron; research grants from Allegro, Apellis, Aura, NEI, NIH, Novartis, OHR Pharmaceuticals, Ophthotech, pSivida, Roche, Santen, SciFluor, Tyrogenex; and consultancies for Alimera Sciences, Alnylam Pharmaceuticals, Bayer, DORC, ONL Therapeutics, Thrombogenics, and Valeant. Clark reports advisory board work, consultancies, research grants, and speaker fees from Genentech/Roche and Regeneron and consultancy for Bayer. Brill reports consultancies for Aries Pharma, Avella, BaroNova, Braeburn Pharmaceuticals, Cardinal Health, Endogastric Solutions, GeneNews, Halt Medical, Lumendi, Medtronic, Monteris Medical, Natera, Phosphorus, Rebiotix, Seno Medical, UCB, Vermillion, Echosens, and HAP Innovations. Brill is a shareholder in EndoChoice, GeneNews, SonarMD, and SynerZ and reports advisory board work with Nestle Health Sciences, Indivior Pharmaceuticals, Eli Lilly, Blue Earth Diagnostics, Bayer, and AstraZeneca. Nielson reports advisory board work/consultancy and research grants for Genentech/Roche; advisory board work and research grants from Regeneron; and research grants from Alcon and Ophthotech.

The Economic Burden of ACPA-Positive Status Among Patients with Rheumatoid Arthritis.

PubMed

Shafrin, Jason; Tebeka, Mahlet Gizaw; Price, Kwanza; Patel, Chad; Michaud, Kaleb

2018-01-01

Anticitrullinated protein antibodies (ACPAs) are serological biomarkers associated with early, rapidly progressing rheumatoid arthritis (RA), including more severe disease and joint damage. ACPA testing has become a routine tool for RA diagnosis and prognosis. Furthermore, treatment efficacy has been shown to vary by ACPA-positive status. However, it is not clear if the economic burden of patients with RA varies by ACPA status. To determine if the economic burden of RA varies by patient ACPA status. IMS PharMetrics Plus health insurance claims and electronic medical record (EMR) data from 2010-2015 were used to identify patients with incident RA. Patients were aged ≥ 18 years, had ≥ 1 inpatient or ≥ 2 outpatient claims reporting an RA diagnosis code (ICD-9-CM code 714.0), and had an anticyclic citrullinated peptide (anti-CCP; a surrogate of ACPA) antibody test within 6 months of diagnosis. Incident patients were defined as those who had no claims with an RA diagnosis code in the 6 months before the first observed RA diagnosis. The primary outcome of interest was RA-related medical expenditures, defined as the sum of payer- and patient-paid amounts for all claims with an RA diagnosis code. Secondary outcomes included health care utilization metrics such as treatment with a disease-modifying antirheumatic drug (DMARD) and physician visits. Generalized linear regression models were used for each outcome, controlling for ACPA-positive status (defined as anti-CCP ≥ 20 AU/mL), age, sex, and Charlson Comorbidity Index score as explanatory variables. Of 647,171 patients diagnosed with RA, 89,296 were incident cases, and 47% (n = 42,285) had an anti-CCP test. After restricting this sample to patients with a linked EMR and reported anti-CCP test result, 859 remained, with 24.7% (n = 212) being ACPA-positive. Compared with ACPA-negative patients, adjusted results showed that ACPA-positive patients were more likely to use either conventional (71.2% vs. 49.6%; P < 0.001) or biologic (20.3% vs. 11.8%; P < 0.001) DMARDs during the first year after diagnosis and had more physician visits (5.58 vs. 3.91 times per year; P < 0.001). Annual RA-associated total expenditures were $7,941 for ACPA-positive and $5,243 for ACPA-negative patients (Δ = $2,698; P = 0.002). RA-associated medical expenditures were $4,380 for ACPA-positive and $3,427 for ACPA-negative patients (Δ = $954; P = 0.168), whereas DMARD expenditures were $3,560 and $1,817, respectively (Δ = $1,743; P = 0.001). RA-related economic burden is higher for patients who are ACPA-positive compared with those who are ACPA-negative. Providers may wish to inform patients diagnosed with ACPA-positive RA about the likely future disease and economic burden in hopes that both stakeholders can be more proactive in addressing them. Funding for this research was contributed by Bristol-Myers Squibb. Patel and Price are employees and stockholders of Bristol-Myers Squibb. Shafrin and Tebeka are employees of Precision Health Economics, a health care consulting firm that received funding from Bristol-Myers Squibb to conduct this study. Michaud has received a grant from Pfizer and is employed by the National Data Bank for Rheumatic Diseases, which has received funds from Amgen, Bristol-Myers Squibb, Eli Lilly, Janssen, Pfizer, and Regeneron. Study concept and design were contributed by Shafrin, Price, Patel, and Michaud. Shafrin, Price, and Patel collected the data, and all authors contributed equally to data analysis. The manuscript was written by Shafrin and Tebeka and revised by Shafrin, Price, Patel, and Michaud.

Exploring Our Low-Mass Neighbors

NASA Astrophysics Data System (ADS)

Kohler, Susanna

2017-10-01

The Karl G. Jansky Very Large Array, located in Socorro, NM. [John Fowler]Taking advantage of a program offered by the National Radio Astronomy Observatory (NRAO), an undergraduate class has observed local dwarf galaxies to learn about their properties.The Benefits of Nearby DwarfsIf you want to learn about the physical properties of low-mass galactic halos, the best place to look is nearby dwarf galaxies. These objects have the benefit of being close enough that we can resolve individual stars, allowing us to explore the relationship between star formation and the surrounding interstellar medium. They also allow us to directly measure bulk velocities, so we can interpret the distributions of both dark and baryonic matt5ter in these galaxies.HI images of UGC 11411. Left: HI mass surface density. Right: the intensity-weighted velocity field of the HI gas, which reveals the bulk kinematics of the galaxy. [Bralts-Kelly et al. 2017]Though thousands of local-volume, gas-rich objects have been explored by gas surveys in the past, many have slipped through the cracks due to the varied selection criteria of these different surveys. In a new study, neutral atomic hydrogen observations are presented for the first time for two of these star-forming, gas-rich dwarf galaxies.A Class in ActionGuided by Professor John Cannon and collaborators at other universities, a class of undergraduates at Macalester College in St. Paul, Minnesota, has coauthored a study of the neutral interstellar medium of these two local dwarf galaxies. The project was made possible by the Observing for University Classes program offered by NRAOs Karl G. Jansky Very Large Array (VLA), in which university classes in observational astronomy can apply for observing time with the VLA.Top: a view of UGC 11411s stars from Hubble. Middle: the locations of the galaxys star formation, as traced by SAOs telescopes observations of H. Bottom: UGC 11411s neutral interstellar medium distribution (red contour), overlaid on the other two data sets. [Bralts-Kelly et al. 2017]The students used the VLA to obtain neutral hydrogen spectral-line observations of UGC 11411 and UGC 8245 in February and March of this year. They then processed and analyzed the data, exploring the stellar population and star formation in each galaxy, and using the galaxies bulk kinematics to calculate their total dynamical masses.Dominated by Dark MatterThe authors found that in both galaxies, the greatest bulk of the neutral interstellar medium can be found in the same location as the ongoing star formation. The two galaxies are different in several ways, however: UGC 8245 has a much lower star formation rate than UGC 11411 currently, and though the neutral hydrogen gas and stellar masses are similar for both galaxies, UGC 11411 has a halo that is more than an order of magnitude more massive.They conclude that UGC 8245 which has a total mass that is only 2 times larger than its baryonic mass is very similar to other low-mass galaxies that have been studied in the past. On the other hand, UGC 11411 which has a total mass that is at least a factor of 10 larger than its baryonic mass is significantly more massive than other known local low-mass galaxies, and it is unusually highly dark-matter dominated.Further explorations of these dwarfs in contrast to one another will continue to reveal information about the low-mass galaxies of the universe.CitationLilly Bralts-Kelly et al 2017 ApJL 848 L10. doi:10.3847/2041-8213/aa8ea0

Baricitinib for Previously Treated Moderate or Severe Rheumatoid Arthritis: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.

PubMed

Ren, Shijie; Bermejo, Iñigo; Simpson, Emma; Wong, Ruth; Scott, David L; Young, Adam; Stevenson, Matt

2018-03-03

As part of its single technology appraisal process, the National Institute for Health and Care Excellence invited the manufacturer (Eli Lilly) of baricitinib (BARI; Olumiant ® ; a Janus kinase inhibitor that is taken orally) to submit evidence of its clinical and cost effectiveness for the treatment of moderate to severe rheumatoid arthritis (RA) after the failure of disease-modifying antirheumatic drugs (DMARDs). The School of Health and Related Research Technology Appraisal Group at the University of Sheffield was commissioned to act as the independent Evidence Review Group (ERG). The ERG produced a detailed review of the evidence for the clinical and cost effectiveness of the technology, based on the company's submission (CS) to NICE. The clinical-effectiveness evidence in the CS for BARI was based predominantly on three randomised controlled trials comparing the efficacy of BARI against adalimumab or placebo, as well as one long-term extension study. The clinical-effectiveness review identified no head-to-head evidence on the efficacy of BARI against all the comparators within the scope. Therefore, the company performed network meta-analyses (NMAs) in two different populations: one in patients who had experienced an inadequate response to conventional DMARDs (cDMARD-IR), and the other in patients who had experienced an inadequate response to tumour necrosis factor inhibitors (TNFi-IR). The company's NMAs concluded BARI had comparable efficacy as the majority of its comparators in both populations. The company submitted a de novo discrete event simulation model that analysed the incremental cost-effectiveness of BARI versus its comparators for the treatment of RA from the perspective of the National Health Service (NHS) in four different populations: (1) cDMARD-IR patients with moderate RA, defined as a 28-Joint Disease Activity Score (DAS28) > 3.2 and no more than 5.1; (2) cDMARD-IR patients with severe RA (defined as a DAS28 > 5.1); (3) TNFi-IR patients with severe RA for whom rituximab (RTX) was eligible; and (4) TNFi-IR patients with severe RA for whom RTX in combination with methotrexate (MTX) is contraindicated or not tolerated. In the cDMARD-IR population with moderate RA, the deterministic incremental cost-effectiveness ratio (ICER) for BARI in combination with MTX compared with intensive cDMARDs was estimated to be £37,420 per quality-adjusted life-year (QALY) gained. In the cDMARD-IR population with severe RA, BARI in combination with MTX dominated all comparators except for certolizumab pegol (CTZ) in combination with MTX, with the ICER of CTZ in combination with MTX compared with BARI in combination with MTX estimated to be £18,400 per QALY gained. In the TNFi-IR population with severe RA, when RTX in combination with MTX was an option, BARI in combination with MTX was dominated by RTX in combination with MTX. In the TNFi-IR population with severe RA for whom RTX in combination with MTX is contraindicated or not tolerated, BARI in combination with MTX dominated golimumab in combination with MTX and was less effective and less expensive than the remaining comparators. Following a critique of the model, the ERG undertook exploratory analyses after applying corrections to the methods used in the NMAs and two programming errors in the economic model that affected the company's probabilistic sensitivity analysis (PSA) results. The ERG's NMA results were broadly comparable with the company's results. The programming error that affected the PSA of the severe cDMARD-IR population had only a minimal impact on the results, while the error affecting the severe TNFi-IR RTX-ineligible population resulted in markedly higher costs and QALYs gained for the affected comparators but did not substantially modify the conclusions of the analysis. The NICE Appraisal Committee concluded that BARI in combination with MTX or as monotherapy is a cost-effective use of NHS resources in patients with severe RA, except in TNFi-IR patients who are RTX-eligible.

Ixekizumab for Treating Moderate-to-Severe Plaque Psoriasis: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.

PubMed

Ramaekers, Bram L T; Wolff, Robert F; Pouwels, Xavier; Oosterhoff, Marije; Van Giessen, Anoukh; Worthy, Gill; Noake, Caro; Armstrong, Nigel; Kleijnen, Jos; Joore, Manuela A

2018-02-26

The National Institute for Health and Care Excellence invited Eli Lilly and Company Ltd, the company manufacturing ixekizumab (tradename Taltz ® ), to submit evidence for the clinical and cost effectiveness of ixekizumab. Ixekizumab was compared with tumour necrosis factor-α inhibitors (etanercept, infliximab, adalimumab), ustekinumab, secukinumab, best supportive care and, if non-biological treatment or phototherapy is suitable, also compared with systemic non-biological therapies and phototherapy with ultraviolet B radiation for adults with moderate-to-severe plaque psoriasis. Kleijnen Systematic Reviews Ltd, in collaboration with Maastricht University Medical Center, was commissioned as the independent Evidence Review Group. This article presents a summary of the company submission, the Evidence Review Group report and the development of the National Institute for Health and Care Excellence guidance for the use of this drug in England and Wales by the Appraisal Committee. The Evidence Review Group produced a critical review of the clinical and cost effectiveness of ixekizumab based on the company submission. The company submission presented three randomised controlled trials identified in a systematic review. All randomised controlled trials were phase III, multicentre placebo-controlled trials including 3866 participants with moderate-to-severe psoriasis. Two trials also included an active comparator (etanercept). All randomised controlled trials showed statistically significant increases in two primary outcomes, static Physician Global Assessment (0,1) and improvement of 75% from baseline in the Psoriasis Area and Severity Index. Ixekizumab was generally well tolerated in the randomised controlled trials, with similar discontinuation rates because of adverse events as placebo or etanercept. The most frequent adverse events of special interest were infections and injection-site reactions. The company submission also included a network meta-analysis of relevant comparators. The Evidence Review Group highlighted some issues regarding the systematic review process and an issue with the generalisability of the findings in that the trials failed to include patients with moderate psoriasis according to a widely used definition. This issue was considered by the Appraisal Committee and the population was deemed generalisable to patients in England and Wales. Based on the network meta-analysis, the Appraisal Committee concluded that ixekizumab was more clinically effective than adalimumab and ustekinumab, and agreed it was likely that ixekizumab was similarly effective compared with secukinumab and infliximab while tolerability was similar to other biological treatments approved for treating psoriasis. The Evidence Review Group's critical assessment of the company's economic evaluation highlighted a number of concerns, including (1) the use of relative outcomes such as Psoriasis Area and Severity Index response to model the cost effectiveness; (2) the exclusion of the consequences of adverse events; (3) the assumption of no utility gain in the induction phase; (4) equal annual discontinuation rates for all treatments; (5) the selection of treatment sequences for consideration in the analyses and; (6) the transparency of the Visual Basic for Applications code used to develop the model. Although some of these issues were adjusted in the Evidence Review Group base case, the Evidence Review Group could not estimate the impact of all of these issues, and thus acknowledges that there are still uncertainties concerning the cost-effectiveness evidence. In the Evidence Review Group base-case incremental analysis, the treatment sequence incorporating ixekizumab in the second line has an incremental cost-effectiveness ratio of £25,532 per quality-adjusted life-year gained vs. the etanercept sequence. Ixekizumab in the first-line sequence has an incremental cost-effectiveness ratio of £39,129 per quality-adjusted life-year gained compared with the treatment sequence incorporating ixekizumab in the second line. Consistent with its conclusion regarding clinical effectiveness, the Appraisal Committee concluded that the cost effectiveness of ixekizumab for treating moderate-to-severe plaque psoriasis was similar to that of other biological treatments, already recommended in previous National Institute for Health and Care Excellence guidance. The committee concluded that the incremental cost-effectiveness ratio was within the range that could be considered a cost-effective use of National Health Service resources.

Olaratumab and doxorubicin versus doxorubicin alone for treatment of soft-tissue sarcoma: an open-label phase 1b and randomised phase 2 trial.

PubMed

Tap, William D; Jones, Robin L; Van Tine, Brian A; Chmielowski, Bartosz; Elias, Anthony D; Adkins, Douglas; Agulnik, Mark; Cooney, Matthew M; Livingston, Michael B; Pennock, Gregory; Hameed, Meera R; Shah, Gaurav D; Qin, Amy; Shahir, Ashwin; Cronier, Damien M; Ilaria, Robert; Conti, Ilaria; Cosaert, Jan; Schwartz, Gary K

2016-07-30

Treatment with doxorubicin is a present standard of care for patients with metastatic soft-tissue sarcoma and median overall survival for those treated is 12-16 months, but few, if any, novel treatments or chemotherapy combinations have been able to improve these poor outcomes. Olaratumab is a human antiplatelet-derived growth factor receptor α monoclonal antibody that has antitumour activity in human sarcoma xenografts. We aimed to assess the efficacy of olaratumab plus doxorubicin in patients with advanced or metastatic soft-tissue sarcoma. We did an open-label phase 1b and randomised phase 2 study of doxorubicin plus olaratumab treatment in patients with unresectable or metastatic soft-tissue sarcoma at 16 clinical sites in the USA. For both the phase 1b and phase 2 parts of the study, eligible patients were aged 18 years or older and had a histologically confirmed diagnosis of locally advanced or metastatic soft-tissue sarcoma not previously treated with an anthracycline, an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, and available tumour tissue to determine PDGFRα expression by immunohistochemistry. In the phase 2 part of the study, patients were randomly assigned in a 1:1 ratio to receive either olaratumab (15 mg/kg) intravenously on day 1 and day 8 plus doxorubicin (75 mg/m(2)) or doxorubicin alone (75 mg/m(2)) on day 1 of each 21-day cycle for up to eight cycles. Randomisation was dynamic and used the minimisation randomisation technique. The phase 1b primary endpoint was safety and the phase 2 primary endpoint was progression-free survival using a two-sided α level of 0.2 and statistical power of 0.8. This study was registered with ClinicalTrials.gov, number NCT01185964. 15 patients were enrolled and treated with olaratumab plus doxorubicin in the phase 1b study, and 133 patients were randomised (66 to olaratumab plus doxorubicin; 67 to doxorubicin alone) in the phase 2 trial, 129 (97%) of whom received at least one dose of study treatment (64 received olaratumab plus doxorubicin, 65 received doxorubicin). Median progression-free survival in phase 2 was 6.6 months (95% CI 4.1-8.3) with olaratumab plus doxorubicin and 4.1 months (2.8-5.4) with doxorubicin (stratified hazard ratio [HR] 0.67; 0.44-1.02, p=0.0615). Median overall survival was 26.5 months (20.9-31.7) with olaratumab plus doxorubicin and 14.7 months (9.2-17.1) with doxorubicin (stratified HR 0.46, 0.30-0.71, p=0.0003). The objective response rate was 18.2% (9.8-29.6) with olaratumab plus doxorubicin and 11.9% (5.3-22.2) with doxorubicin (p=0.3421). Steady state olaratumab serum concentrations were reached during cycle 3 with mean maximum and trough concentrations ranging from 419 μg/mL (geometric coefficient of variation in percentage [CV%] 26.2) to 487 μg/mL (CV% 33.0) and from 123 μg/mL (CV% 31.2) to 156 μg/mL (CV% 38.0), respectively. Adverse events that were more frequent with olaratumab plus doxorubicin versus doxorubicin alone included neutropenia (37 [58%] vs 23 [35%]), mucositis (34 [53%] vs 23 [35%]), nausea (47 [73%] vs 34 [52%]), vomiting (29 [45%] vs 12 [18%]), and diarrhoea (22 [34%] vs 15 [23%]). Febrile neutropenia of grade 3 or higher was similar in both groups (olaratumab plus doxorubicin: eight [13%] of 64 patients vs doxorubicin: nine [14%] of 65 patients). This study of olaratumab with doxorubicin in patients with advanced soft-tissue sarcoma met its predefined primary endpoint for progression-free survival and achieved a highly significant improvement of 11.8 months in median overall survival, suggesting a potential shift in the treatment of soft-tissue sarcoma. Eli Lilly and Company. Copyright © 2016 Elsevier Ltd. All rights reserved.

Relationships Between Functional Outcomes and Symptomatic Improvement in Atomoxetine-Treated Adult Patients with Attention-Deficit/Hyperactivity Disorder: Post Hoc Analysis of an Integrated Database.

PubMed

De Bruyckere, Katrien; Bushe, Chris; Bartel, Christoph; Berggren, Lovisa; Kan, Cornelis C; Dittmann, Ralf W

2016-06-01

Atomoxetine treatment is associated with improvements in functional outcomes in patients with attention-deficit/hyperactivity disorder (ADHD), although relationships between improvements in these outcomes and reductions in ADHD symptoms have not been comprehensively investigated in adults. The aim of this study was to assess relationships between functional outcomes and ADHD symptoms (primary objective), and to assess time courses of changes in functional outcomes from baseline to weeks 10 and 24 (secondary objective). We analyzed data pooled from seven Eli Lilly-sponsored placebo-controlled trials of atomoxetine in adults with ADHD that had Conners' Adult ADHD Rating Scales-Investigator Rated: Screening Version (CAARS-Inv:SV) total scores and functional outcome data at baseline and at week 10. Two trials also had these data at week 24. Patients were included in these pooled analyses if they had a CAARS-Inv:SV total score at baseline and at one or more post-baseline visits at weeks 10 or 24, or had post-baseline scores that would allow missing scores at weeks 10 or 24 to be imputed. To address the primary objective, changes in functional outcomes during treatment with atomoxetine versus placebo were assessed using last observation carried forward (LOCF) analysis of covariance (ANCOVA) and mixed-effects model repeated measures (MMRM) analysis, and correlations between score changes in CAARS-Inv:SV total and functional outcomes were assessed using Spearman's rank correlation coefficient (r) at weeks 10 and 24. The secondary objective was addressed using MMRM. At baseline, patients generally had moderately severe or worse ADHD symptoms (based on CAARS-Inv:SV total scores) and impaired functional outcomes (based on Adult ADHD Quality-of-Life [AAQoL], Behavior Rating Inventory of Executive Function-Adult Version [BRIEF-A], Sheehan Disability Scale [SDS], and 36-item Short-Form Health Survey [SF-36] scores). These baseline characteristics were comparable in the atomoxetine and placebo groups. For atomoxetine versus placebo, statistically significant improvements were detected in AAQoL total and subscores at weeks 10 and 24, and in BRIEF-A Self-Report scores at week 10, but not in BRIEF-A Informant Report or SDS scores at week 10 (no BRIEF-A or SDS data were available at week 24), and not in SF-36 at weeks 10 or 24. All functional improvements were gradual. During treatment with atomoxetine, there were moderate correlations between reductions in CAARS-Inv:SV total scores and increases in AAQoL total and subscores at weeks 10 and 24 (r range -0.58 to -0.39; n = 394-545), and also with reductions in BRIEF-A Self-Report at week 10 (r = 0.49; n = 256). With placebo, moderate correlations were also found between reductions in CAARS-Inv:SV total scores and increases in AAQoL total and subscores at weeks 10 and 24 (r range -0.56 to -0.28; n = 321-542), and with reductions in BRIEF-A Self-Report at week 10 (r = 0.49; n = 271). However, correlations between changes in CAARS-Inv:SV and BRIEF-A Informant at week 10 were low for atomoxetine-treated patients (r = 0.25; n = 65), moderate with placebo (r = 0.42; n = 72), and there were low/no correlations between changes in CAARS-Inv:SV and functional outcome rating scales that are not specific to ADHD; that is, for atomoxetine-treated patients, SDS total r = 0.19 (n = 32 at week 10) and SF-36 r range - 0.20 to -0.01 (n = 51 at week 10, n = 183 at week 24). Atomoxetine-treated adult patients experienced improvements in functional outcomes (AAQoL and BRIEF-A Self-Report) that correlated with reductions in ADHD symptoms. Although atomoxetine improved both the ADHD symptoms and functional outcomes, the correlation between symptoms and functional outcomes was low to moderate, suggesting that they measure overlapping but different aspects of the disorder. Hence, clinicians should assess not just ADHD symptoms, but also the functional impairments.

AMCP Partnership Forum: Enabling the Exchange of Clinical and Economic Information Pre-FDA Approval.

PubMed

2017-01-01

Current federal laws and FDA regulations have significantly restricted the sharing of clinical and health economic information on biopharmaceuticals that have yet to receive FDA approval. Over the past several years, organizations that make health care coverage decisions, including those that set copayments, premiums, and formulary placement, have expressed a need for receiving this information before approval, as long as appropriate safeguards exist to prevent this information from reaching unintended entities. Population health decision makers have indicated that waiting until FDA approval is often too late for the critical planning, budgeting, and forecasting associated with health benefit design, especially given the recent influx of high-cost medications and scrutiny for better evaluation and preparation. Recognizing that securities laws restrict the disclosure of nonpublic information and may need to be amended, permissible early dissemination would allow population health decision makers to incorporate clinical and economic information for pipeline drugs or expanded indications into financial forecasting for the following year's plan. Access to this information is needed 12-18 months before FDA approval when organizations are deciding on terms of coverage and budgetary assumptions for state health insurance rate filings, Medicare and Medicaid bids, contracts with health care purchasers, and other financial arrangements. The need for exchange of clinical economic information before FDA approval was first introduced at a previous Academy of Managed Care (AMCP) forum in March 2016, which addressed section 114 of the Food and Drug Administration Modernization Act and the communication of such information after FDA approval. To address preapproval information specifically, AMCP convened a Partnership Forum on September 13-14, 2016. This forum included a diverse group of stakeholders representing managed care, the biopharmaceutical industry, providers, patients, health economists, academia, and others. The multistakeholder group represented the key professionals and entities affected by the federal laws and FDA regulations that restrict the sharing of preapproval information and the collective credibility necessary for proposing this new communication process. Forum participants primarily focused on 6 items of discussion: (1) creating and defining new terms for how biopharmaceutical manufacturers may provide clinical and economic information 12-18 months before FDA approval; (2) defining the clinical and scientific standards that this information should meet; (3) determining which entities should have access to this information and the value to each; (4) the format and process by which this information should be disseminated; (5) developing definitions for existing terms referenced in current laws, regulations, or guidance documents that would need to be modernized to align with the identified new term; and (6) providing safeguards to prevent this information from reaching unintended entities. Forum participants selected "preapproval information exchange" (PIE) as the correct term to describe this proposed new communication process and to be inclusive of data from pivotal phase III clinical trials, pharmaco-economic data, and patient-reported outcomes, as well as other relevant items, including anticipated indications, place in therapy, and routes of administration. Stakeholders agreed that PIE should be truthful, non-misleading, and include a broad range of information to meet the needs of population health decision makers and health care technology evolution. Recipients of PIE would be limited to population health decision makers who need this information for coverage decisions. The format and process for PIE disseminated should allow for a bidirectional exchange between manufacturers and population health decision makers but should not be proscribed in legislation. Furthermore, new legislative language may be beneficial, since PIE is a novel category of information. New legislation could provide a safe harbor and clarity that PIE does not violate preapproval promotion and the Federal Food, Drug, and Cosmetic Act and its regulations. The AMCP Partnership Forum on Enabling the Exchange of Clinical and Economic Data Pre-FDA Approval and the development of this proceedings document were supported by AbbVie, Boehringer Ingelheim Pharmaceuticals, Bristol-Myers Squibb, Celgene, Intarcia Therapeutics, Eli Lilly and Company, GlaxoSmithKline, Merck, National Pharmaceutical Council, Novo Nordisk, Pfizer, Pharmaceutical Research and Manufacturers of America, Precision for Value, Sanofi, Takeda Pharmaceuticals, U.S.A., and Xcenda. All sponsors participated in the forum and in revising and approving the manuscript.

Personalized Care and the Role of Insulin as a Vehicle to Optimizing Treatments in Diabetes Care.

PubMed

Bieszk, Nella; Grabner, Michael; Wei, Wenhui; Barron, John; Quimbo, Ralph; Yan, Tingjian; Biel, Beth; Chu, James W

2017-11-01

In patients with type 2 diabetes (T2D) with poor glycemic control, there is an unmet need for treatment optimization involving the initiation and/or intensification of insulin therapy, which is often delayed because of clinical inertia. Educational initiatives that target patients and physicians might be one way to address this need. To evaluate the effectiveness of educational materials mailed to physicians and their patients in affecting initiation of insulin therapy and other health care outcomes. This study, named PIVOTs (Personalized care and the role of Insulin as a Vehicle to Optimizing Treatments), used integrated medical and pharmacy claims data from the U.S.-based HealthCore Integrated Research Database between January 1, 2006, and April 4, 2014, to identify patients who were potential candidates for insulin therapy. Eligible patients were aged 18-75 years, currently enrolled in a commercial or Medicare Advantage health plan, with T2D diagnosis codes. Patients selected for insulin treatment education had glycated hemoglobin A1c (A1c) > 10%, irrespective of the number of noninsulin antihyperglycemic drugs used, or A1c > 8.0% and ≤ 10% while receiving ≥ 2 noninsulin antihyperglycemic drugs. For each identified patient, a corresponding treating physician was identified on a hierarchical basis. Physician-level randomization was conducted to assign physicians and their linked patients to the following 4 cohorts: (1) a cross-sectional cohort in which educational materials were sent to patients and physicians on a single outreach date; (2) a longitudinal cohort in which educational materials were sent to patients and physicians on 2 occasions, 3 months apart; (3) an enhanced cohort in which patients and physicians received the same mailings as the longitudinal cohort, plus physicians were invited to attend a 1:1 video conference academic detailing session; and (4) a control cohort in which patients and physicians did not receive any educational materials. Insulin initiation rates, A1c levels, and medical and pharmacy costs were assessed from claims over 6 and 12 months follow-up within each cohort. Mean insulin initiation rates at 12 months ranged from 9.2%-10.3% (all patients) to 12.3%-14.9% (subset with baseline A1c ≥ 9.0%), with similar rates across the intervention and control cohorts. Reductions in A1c from baseline were also similar across cohorts for all patients (0.1%-0.6%), as well as for those with a baseline A1c ≥ 9.0% (0.9%-1.6%). Approximately 14%-20% of patients achieved A1c < 7.0%, with no differences across cohorts. Changes in mean total all-cause and diabetes-related health care costs were also similar across cohorts. The findings of this real-world, randomized intervention call into question the value of educational mailings as a means to overcoming clinical inertia and improving health outcomes in patients with T2D, at least in the context of insulin initiation. This study was funded by Sanofi US. Bieszk and Wei are employees of Sanofi US. Grabner, Barron, and Quimbo are employees of HealthCore, which was under contract with Sanofi US for the conduct of this study. Yan is an employee of PHAR, LLC and was employed by HealthCore at the time this study was conducted and completed. Biel is an employee of Anthem. Chu is a consultant for Sanofi US; a member of the lecture bureaus for AstraZeneca, Eli Lilly, and Sanofi US; and has received research funding from Novo Nordisk. Study concept and design were contributed by Bieszk, Grabner, Wei, Quimbo, and Barron. Yan, Barron, Quimbo, and Grabner collected the data, which were interpreted by Biel, Chu, Bieszk, and Wei, with assistance from the other authors. The manuscript was written by Bieszk, with assistance from the other authors, and revised by Bieszk, Grabner, Biel, and Chu, along with the other authors. Part of this work was presented in poster format at the 76th Scientific Sessions of the American Diabetes Association; June 10-14, 2016; New Orleans, Louisiana.

Neoadjuvant plus adjuvant bevacizumab in early breast cancer (NSABP B-40 [NRG Oncology]): secondary outcomes of a phase 3, randomised controlled trial.

PubMed

Bear, Harry D; Tang, Gong; Rastogi, Priya; Geyer, Charles E; Liu, Qing; Robidoux, André; Baez-Diaz, Luis; Brufsky, Adam M; Mehta, Rita S; Fehrenbacher, Louis; Young, James A; Senecal, Francis M; Gaur, Rakesh; Margolese, Richard G; Adams, Paul T; Gross, Howard M; Costantino, Joseph P; Paik, Soonmyung; Swain, Sandra M; Mamounas, Eleftherios P; Wolmark, Norman

2015-09-01

NSABP B-40 was a 3 × 2 factorial trial testing whether adding capecitabine or gemcitabine to docetaxel followed by doxorubicin plus cyclophosphamide neoadjuvant chemotherapy would improve outcomes in women with operable, HER2-negative breast cancer and whether adding neoadjuvant plus adjuvant bevacizumab to neoadjuvant chemotherapy regimens would also improve outcomes. As reported previously, addition of neoadjuvant bevacizumab increased the proportion of patients achieving a pathological complete response, which was the primary endpoint. We present secondary patient outcomes, including disease-free survival, a specified endpoint by protocol, and data for distant recurrence-free interval, and overall survival, which were not prespecified endpoints but were collected prospectively. In this randomised controlled trial (NSABP B-40), we enrolled women aged 18 years or older, with operable, HER2-non-amplified invasive adenocarcinoma of the breast, 2 cm or greater in diameter by palpation, clinical stage T1c-3, cN0, cN1, or cN2a, without metastatic disease and diagnosed by core needle biopsy. Patients received one of three docetaxel-based neoadjuvant regimens for four cycles: docetaxel alone (100 mg/m(2)) with addition of capecitabine (825 mg/m(2) oral twice daily days 1-14, 75 mg/m(2) docetaxel) or with addition of gemcitabine (1000 mg/m(2) days 1 and 8 intravenously, 75 mg/m(2) docetaxel), all followed by neoadjuvant doxorubicin and cyclophosphamide (60 mg/m(2) and 600 mg/m(2) intravenously) every 3 weeks for four cycles. Those randomly assigned to bevacizumab groups were to receive bevacizumab (15 mg/kg, every 3 weeks for six cycles) with neoadjuvant chemotherapy and postoperatively for ten doses. Randomisation was done (1:1:1:1:1:1) via a biased-coin minimisation procedure to balance the characteristics with respect to clinical nodal status, clinical tumour size, hormone receptor status, and age. Intent-to-treat analyses were done for disease-free survival and overall survival. This study is registered with ClinicalTrials.gov, number NCT00408408. Between Jan 5, 2007, and June 30, 2010, 1206 patients were enrolled in the study. Follow-up data were collected from Oct 31, 2007 to March 27, 2014, and were available for overall survival in 1186 patients, disease-free survival in 1184, and distant recurrence-free interval in 1181. Neither capecitabine nor gemcitabine increased disease-free survival or overall survival. Median follow-up was 4·7 years (IQR 4·0-5·2). The addition of bevacizumab significantly increased overall survival (hazard ratio 0·65 [95% CI 0·49-0·88]; p=0·004) but did not significantly increase disease-free survival (0·80 [0·63-1·01]; p=0·06). Four deaths occurred on treatment due to vascular disorder (docetaxel plus capecitabine followed by doxorubicin plus cyclophosphamide group), sudden death (docetaxel plus capecitabine followed by doxorubicin plus cyclophosphamide group), infective endocarditis (docetaxel plus bevacizumab followed by doxorubicin plus cyclophosphamide and bevacizumab group), and visceral arterial ischaemia (docetaxel followed by doxorubicin plus cyclophosphamide group). The most common grade 3-4 adverse events in the bevacizumab group were neutropenia (grade 3, 99 [17%]; grade 4, 37 [6%]), hand-foot syndrome (grade 3, 63 [11%]), and hypertension (grade 3, 60 [10%]; grade 4, two [<1%]) and in the non-bevacizumab group were neutropenia (grade 3, 98 [16%]; grade 4, 36 [6%]), fatigue (grade 3, 53 [9%]), and hand-foot syndrome (grade 3, 43 [7%]). The addition of gemcitabine or capecitabine to neoadjuvant docetaxel plus doxorubicin plus cyclophosphamide does not seem to provide any benefit to patients with operable breast cancer, and should not change clinical practice in the short term. The improved overall survival with bevacizumab contradicts the findings of other studies of bevacizumab in breast cancer and may indicate the need for additional investigation of this agent. National Institutes of Health, Genentech, Roche Laboratories, Lilly Research Laboratories, and Precision Therapeutics. Copyright © 2015 Elsevier Ltd. All rights reserved.

Racial and Ethnic Disparities in Meeting MTM Eligibility Criteria Based on Star Ratings Compared with the Medicare Modernization Act.

PubMed

Spivey, Christina A; Wang, Junling; Qiao, Yanru; Shih, Ya-Chen Tina; Wan, Jim Y; Kuhle, Julie; Dagogo-Jack, Samuel; Cushman, William C; Chisholm-Burns, Marie

2018-02-01

Previous research found racial and ethnic disparities in meeting medication therapy management (MTM) eligibility criteria implemented by the Centers for Medicare & Medicaid Services (CMS) in accordance with the Medicare Modernization Act (MMA). To examine whether alternative MTM eligibility criteria based on the CMS Part D star ratings quality evaluation system can reduce racial and ethnic disparities. This study analyzed the Beneficiary Summary File and claims files for Medicare beneficiaries linked to the Area Health Resource File. Three million Medicare beneficiaries with continuous Parts A, B, and D enrollment in 2012-2013 were included. Proposed star ratings criteria included 9 existing medication safety and adherence measures developed mostly by the Pharmacy Quality Alliance. Logistic regression and the Blinder-Oaxaca approach were used to test disparities in meeting MMA and star ratings eligibility criteria across racial and ethnic groups. Multinomial logistic regression was used to examine whether there was a disparity reduction by comparing individuals who were MTM-eligible under MMA but not under star ratings criteria and those who were MTM-eligible under star ratings criteria but not under the MMA. Concerning MMA-based MTM criteria, main and sensitivity analyses were performed to represent the entire range of the MMA eligibility thresholds reported by plans in 2009, 2013, and proposed by CMS in 2015. Regarding star ratings criteria, meeting any 1 of the 9 measures was examined as the main analysis, and various measure combinations were examined as the sensitivity analyses. In the main analysis, adjusted odds ratios for non-Hispanic blacks (backs) and Hispanics to non-Hispanic whites (whites) were 1.394 (95% CI = 1.375-1.414) and 1.197 (95% CI = 1.176-1.218), respectively, under star ratings. Blacks were 39.4% and Hispanics were 19.7% more likely to be MTM-eligible than whites. Blacks and Hispanics were less likely to be MTM-eligible than whites in some sensitivity analyses. Disparities were not completely explained by differences in patient characteristics based on the Blinder-Oaxaca approach. The multinomial logistic regression of each main analysis found significant adjusted relative risk ratios (RRR) between whites and blacks for 2009 (RRR = 0.459, 95% CI = 0.438-0.481); 2013 (RRR = 0.449, 95% CI = 0.434-0.465); and 2015 (RRR = 0.436, 95% CI = 0.425-0.446) and between whites and Hispanics for 2009 (RRR = 0.559, 95% CI = 0.528-0.593); 2013 (RRR = 0.544, 95% CI = 0.521-0.569); and 2015 (RRR = 0.503, 95% CI = 0.488-0.518). These findings indicate a significant reduction in racial and ethnic disparities when using star ratings eligibility criteria; for example, black-white disparities in the likelihood of meeting MTM eligibility criteria were reduced by 55.1% based on star ratings compared with MMA in 2013. Similar patterns were found in most sensitivity and disease-specific analyses. This study found that minorities were more likely than whites to be MTM-eligible under the star ratings criteria. In addition, MTM eligibility criteria based on star ratings would reduce racial and ethnic disparities associated with MMA in the general Medicare population and those with specific chronic conditions. Research reported in this publication was supported by the National Institute on Aging of the National Institutes of Health under award number R01AG049696. The content of this study is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Cushman reports an Eli Lilly grant and uncompensated consulting for Takeda Pharmaceuticals outside this work. The other authors have no potential conflicts of interest to report. Study concept and design were contributed by Wang and Shih, along with Wan, Kuhle, Spivey, and Cushman. Wang, Qiao, and Wan took the lead in data collection, with assistance from the other authors. Data interpretation was performed by Wang, Kuhle, and Qiao, with assistance from the other authors. The manuscript was written by Spivey and Qiao, along with the other authors, and revised by Cushman, Dagogo-Jack, and Chisholm-Burns, along with the other authors.

Effect of an intensified multifactorial intervention on cardiovascular outcomes and mortality in type 2 diabetes (J-DOIT3): an open-label, randomised controlled trial.

PubMed

Ueki, Kohjiro; Sasako, Takayoshi; Okazaki, Yukiko; Kato, Masayuki; Okahata, Sumie; Katsuyama, Hisayuki; Haraguchi, Mikiko; Morita, Ai; Ohashi, Ken; Hara, Kazuo; Morise, Atsushi; Izumi, Kazuo; Ishizuka, Naoki; Ohashi, Yasuo; Noda, Mitsuhiko; Kadowaki, Takashi

2017-12-01

Limited evidence suggests that multifactorial interventions for control of glucose, blood pressure, and lipids reduce macrovascular complications and mortality in patients with type 2 diabetes. However, safe and effective treatment targets for these risk factors have not been determined for such interventions. In this multicentre, open-label, randomised, parallel-group trial, undertaken at 81 clinical sites in Japan, we randomly assigned (1:1) patients with type 2 diabetes aged 45-69 years with hypertension, dyslipidaemia, or both, and an HbA 1c of 6·9% (52·0 mmol/mol) or higher, to receive conventional therapy for glucose, blood pressure, and lipid control (targets: HbA 1c <6·9% [52·0 mmol/mol], blood pressure <130/80 mm Hg, LDL cholesterol <120 mg/dL [or 100 mg/dL in patients with a history of coronary artery disease]) or intensive therapy (HbA 1c <6·2% [44·3 mmol/mol], blood pressure <120/75 mm Hg, LDL cholesterol <80 mg/dL [or 70 mg/dL in patients with a history of coronary artery disease]). Randomisation was done using a computer-generated, dynamic balancing method, stratified by sex, age, HbA 1c , and history of cardiovascular disease. Neither patients nor investigators were masked to group assignment. The primary outcome was occurrence of any of a composite of myocardial infarction, stroke, revascularisation (coronary artery bypass surgery, percutaneous transluminal coronary angioplasty, carotid endarterectomy, percutaneous transluminal cerebral angioplasty, and carotid artery stenting), and all-cause mortality. The primary analysis was done in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT00300976. Between June 16, 2006, and March 31, 2009, 2542 eligible patients were randomly assigned to intensive therapy or conventional therapy (1271 in each group) and followed up for a median of 8·5 years (IQR 7·3-9·0). Two patients in the intensive therapy group were found to be ineligible after randomisation and were excluded from the analyses. During the intervention period, mean HbA 1c , systolic blood pressure, diastolic blood pressure, and LDL cholesterol concentrations were significantly lower in the intensive therapy group than in the conventional therapy group (6·8% [51·0 mmol/mol] vs 7·2% [55·2 mmol/mol]; 123 mm Hg vs 129 mm Hg; 71 mm Hg vs 74 mm Hg; and 85 mg/dL vs 104 mg/dL, respectively; all p<0·0001). The primary outcome occurred in 109 patients in the intensive therapy group and in 133 patients in the conventional therapy group (hazard ratio [HR] 0·81, 95% CI 0·63-1·04; p=0·094). In a post-hoc breakdown of the composite outcome, frequencies of all-cause mortality (HR 1·01, 95% CI 0·68-1·51; p=0·95) and coronary events (myocardial infarction, coronary artery bypass surgery, and percutaneous transluminal coronary angioplasty; HR 0·86, 0·58-1·27; p=0·44) did not differ between groups, but cerebrovascular events (stroke, carotid endarterectomy, percutaneous transluminal cerebral angioplasty, and carotid artery stenting) were significantly less frequent in the intensive therapy group (HR 0·42, 0·24-0·74; p=0·002). Apart from non-severe hypoglycaemia (521 [41%] patients in the intensive therapy group vs 283 [22%] in the conventional therapy group, p<0·0001) and oedema (193 [15%] vs 129 [10%], p=0·0001), the frequencies of major adverse events did not differ between groups. Our results do not fully support the efficacy of further intensified multifactorial intervention compared with current standard care for the prevention of a composite of coronary events, cerebrovascular events, and all-cause mortality. Nevertheless, our findings suggest a potential benefit of an intensified intervention for the prevention of cerebrovascular events in patients with type 2 diabetes. Ministry of Health, Labour and Welfare of Japan, Asahi Kasei Pharma, Astellas Pharma, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Eli Lilly, GlaxoSmithKline, Kissei Pharmaceutical, Kowa Pharmaceutical, Mitsubishi Tanabe Pharma, Mochida Pharmaceutical, MSD, Novartis Pharma, Novo Nordisk, Ono Pharmaceutical, Pfizer, Sanwa Kagaku Kenkyusho, Shionogi, Sumitomo Dainippon Pharma, Taisho Toyama Pharmaceutical, and Takeda. Copyright © 2017 Elsevier Ltd. All rights reserved.

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease: an exploratory analysis from the EMPA-REG OUTCOME randomised, placebo-controlled trial.

PubMed

Cherney, David Z I; Zinman, Bernard; Inzucchi, Silvio E; Koitka-Weber, Audrey; Mattheus, Michaela; von Eynatten, Maximilian; Wanner, Christoph

2017-08-01

In a pooled analysis of short-term trials, short-term treatment with the sodium-glucose co-transporter-2 (SGLT2) inhibitor empagliflozin reduced albuminuria in patients with type 2 diabetes and prevalent albuminuria. In this exploratory analysis of the EMPA-REG OUTCOME trial, we report the short-term and long-term effects of empagliflozin on albuminuria in patients with type 2 diabetes and established cardiovascular disease, according to patients' baseline albuminuria status. In this randomised, double-blind, placebo-controlled trial at 590 sites in 42 countries, we randomly assigned patients aged 18 years and older with type 2 diabetes and established cardiovascular disease (1:1:1) to empagliflozin 10 mg, empagliflozin 25 mg, or placebo in addition to standard of care until at least 691 patients experienced an adjudicated event included in the primary outcome. We did the randomisation with a computer-generated random-sequence and interactive voice-response and web-response system, stratified by HbA 1c , BMI, region, and estimated glomerular filtration rate. Patients, investigators, and individuals involved in analysis of trial data were masked to treatment assignment. The primary and secondary efficacy and safety endpoints of this trial have been reported previously. Here, we report urinary albumin-to-creatinine ratio (UACR) data for the pooled empagliflozin group versus placebo according to albuminuria status at baseline (normoalbuminuria: UACR <30 mg/g; microalbuminuria: UACR ≥30 to ≤300 mg/g; and macroalbuminuria: UACR >300 mg/g). We did the analysis with mixed-model repeated measures including prespecified and post-hoc tests. This study is completed and registered with ClinicalTrials.gov, number NCT01131676. Between Sept 1, 2010, and April 22, 2013, we randomly assigned 7028 patients to treatment groups and 7020 patients received treatment. At baseline, we had UACR data for 6953 patients: 4171 (59% of treated patients; 1382 assigned to placebo and 2789 assigned to empagliflozin) had normoalbuminuria, 2013 (29%; 675 assigned to placebo and 1338 assigned to empagliflozin) had microalbuminuria, and 769 (11%; 260 assigned to placebo and 509 assigned to empagliflozin) had macroalbuminuria. Median treatment duration was 2·6 years (IQR 2·0-3·4; 136 weeks) and median observation time was 3·1 years (2·2-3·6; 164 weeks). After short-term treatment at week 12, the placebo-adjusted geometric mean ratio of UACR change from baseline with empagliflozin was -7% (95% CI -12 to -2; p=0·013) in patients with normoalbuminuria, -25% (-31 to -19; p<0·0001) in patients with microalbuminuria, and -32% (-41 to -23; p<0·0001) in patients with macroalbuminuria. The reductions in UACR were maintained with empagliflozin in all three groups compared with placebo during long-term treatment when measured at 164 weeks. At follow-up, after cessation of treatment for a median of 34 or 35 days, UACR was lower in the empagliflozin versus placebo group in those with baseline microalbuminuria (placebo-corrected adjusted geometric mean ratio of relative change from baseline with empagliflozin: -22%, 95% CI -32 to -11; p=0·0003) or macroalbuminuria (-29%, -44 to -10; p=0·0048), but not for patients with baseline normoalbuminuria (1%, -8 to 10; p=0·8911). Patients treated with empagliflozin were more likely to experience a sustained improvement from microalbuminuria to normoalbuminuria (hazard ratio [HR] 1·43, 95% CI 1·22 to 1·67; p<0·0001) or from macroalbuminuria to microalbuminuria or normoalbuminuria (HR 1·82, 1·40 to 2·37; p<0·0001), and less likely to experience a sustained deterioration from normoalbuminuria to microalbuminuria or macroalbuminuria (HR 0·84, 0·74 to 0·95; p=0·0077). The proportions of patients with any adverse events, serious adverse events, and adverse events leading to discontinuation increased with worsening UACR status at baseline, but were similar between treatment groups. The proportion of patients with genital infections was greater with empagliflozin than placebo in all subgroups by UACR status. These results support short-term and long-term benefits of empagliflozin on urinary albumin excretion, irrespective of patients' albuminuria status at baseline. Boehringer Ingelheim & Eli Lilly and Company Diabetes Alliance. Copyright © 2017 Elsevier Ltd. All rights reserved.

Dulaglutide as add-on therapy to SGLT2 inhibitors in patients with inadequately controlled type 2 diabetes (AWARD-10): a 24-week, randomised, double-blind, placebo-controlled trial.

PubMed

Ludvik, Bernhard; Frías, Juan P; Tinahones, Francisco J; Wainstein, Julio; Jiang, Honghua; Robertson, Kenneth E; García-Pérez, Luis-Emilio; Woodward, D Bradley; Milicevic, Zvonko

2018-05-01

Glucagon-like peptide-1 (GLP-1) receptor agonists and sodium-glucose co-transporter-2 (SGLT2) inhibitors improve glycaemic control and reduce bodyweight in patients with type 2 diabetes through different mechanisms. We assessed the safety and efficacy of the addition of the once-weekly GLP-1 receptor agonist dulaglutide to the ongoing treatment regimen in patients whose diabetes is inadequately controlled with SGLT2 inhibitors, with or without metformin. AWARD-10 was a phase 3b, double-blind, parallel-arm, placebo-controlled, 24-week study done at 40 clinical sites in Austria, Czech Republic, Germany, Hungary, Israel, Mexico, Spain, and the USA. Eligible adult patients (≥18 years) with inadequately controlled type 2 diabetes (HbA 1c concentration ≥7·0% [53 mmol/mol] and ≤9·5% [80 mmol/mol]), a BMI of 45 kg/m 2 or less, and taking stable doses (>3 months) of an SGLT2 inhibitor (with or without metformin) were randomly assigned (1:1:1) via an interactive web-response system to subcutaneous injections of either dulaglutide 1·5 mg, dulaglutide 0·75 mg, or placebo once per week for 24 weeks. Patients and investigators were masked to dulaglutide and placebo assignment, and those assessing outcomes were masked to study drug assignment. The primary objective was to test for the superiority of dulaglutide (1·5 mg or 0·75 mg) versus placebo for change in HbA 1c concentration from baseline at 24 weeks. All analyses were done in the intention-to-treat population, defined as all randomly assigned patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT02597049. Between Dec 7, 2015, and Feb 3, 2017, 424 patients were randomly assigned to dulaglutide 1·5 mg (n=142), dulaglutide 0·75 mg (n=142), and placebo (n=140). One patient in the dulaglutide 0·75 mg group was excluded from the analysis because they did not receive any dose of the study drug. The reduction in HbA 1c concentration at 24 weeks was larger in patients receiving dulaglutide (least squares mean [LSM] for dulaglutide 1·5 mg -1·34% [SE 0·06] or -14·7 mmol/mol [0·6]; dulaglutide 0·75 mg -1·21% [0·06] or -13·2 mmol/mol [0·6]) than in patients receiving placebo (-0·54% [0·06] or -5·9 mmol/mol [0·6]; p<0·0001 for both groups vs placebo). The LSM differences were -0·79% (95% CI -0·97 to -0·61) or -8·6 mmol/mol (-10·6 to -6·7) for dulaglutide 1·5 mg and -0·66% (-0·84 to -0·49) or -7·2 mmol/mol (-9·2 to -5·4) for dulaglutide 0·75 mg (p<0·0001 for both). Serious adverse events were reported for five (4%) patients in the dulaglutide 1·5 mg group, three (2%) patients in the dulaglutide 0·75 mg group, and five (4%) patients in the placebo group. Treatment-emergent adverse events were more common in patients treated with dulaglutide than in patients who received placebo, mainly because of an increased incidence of gastrointestinal adverse events. Nausea (21 [15%] patients in the dulaglutide 1·5 mg group vs seven [5%] in the dulaglutide 0·75 mg group vs five [4%] in the placebo group), diarrhoea (eight [6%] vs 14 [10%] vs four [3%]), and vomiting (five [4%] vs four [3%] vs one [1%]) were more common with dulaglutide than with placebo. One episode of severe hypoglycaemia was reported in the dulaglutide 0·75 mg group. Two (1%) patients receiving dulaglutide 1·5 mg died, but these deaths were not considered to be related to study drug; no deaths occurred in the other groups. Dulaglutide as add-on treatment to SGLT2 inhibitors (with or without metformin) resulted in significant and clinically relevant improvements in glycaemic control, with acceptable tolerability that is consistent with the established safety profile of dulaglutide. Eli Lilly and Company. Copyright © 2018 Elsevier Ltd. All rights reserved.

Antisense oligodeoxynucleotide inhibition as a potent diagnostic tool for gene function in plant biology

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

Jansson, Christer; Sun, Chuanxin; Ghebramedhin, Haile

Antisense oligodeoxynucleotide (ODN) inhibition emerges as an effective means for probing gene function in plant cells. Employing this method we have established the importance of the SUSIBA2 transcription factor for regulation of starch synthesis in barley endosperm, and arrived at a model for the role of the SUSIBAs in sugar signaling and source-sink commutation during cereal endosperm development. In this addendum we provide additional data demonstrating the suitability of the antisense ODN technology in studies on starch branching enzyme activities in barley leaves. We also comment on the mechanism for ODN uptake in plant cells. Antisense ODNs are short (12-25more » nt-long) stretches of single-stranded ODNs that hybridize to the cognate mRNA in a sequence-specific manner, thereby inhibiting gene expression. They are naturally occurring in both prokaryotes and eukaryotes where they partake in gene regulation and defense against viral infection. The mechanisms for antisense ODN inhibition are not fully understood but it is generally considered that the ODN either sterically interferes with translation or promotes transcript degradation by RNase H activation. The earliest indication of the usefulness of antisense ODN technology for the purposes of molecular biology and medical therapy was the demonstration in 1978 that synthetic ODNs complementary to Raos sarcoma virus could inhibit virus replication in tissue cultures of chick embryo fibroblasts. Since then the antisense ODN technology has been widely used in animal sciences and as an important emerging therapeutic approach in clinical medicine. However, antisense ODN inhibition has been an under-exploited strategy for plant tissues, although the prospects for plant cells in suspension cultures to take up single-stranded ODNs was reported over a decade ago. In 2001, two reports from Malho and coworker demonstrated the use of cationic-complexed antisense ODNs to suppress expression of genes encoding pollen-signaling proteins in pollen tubes from the lilly Agapanthus umbellatus. For the uptake of DNA pollen tubes represent a unique system since the growing tip is surrounded by a loose matrix of hemicellulose and pectins, exposing the plasma membrane7 and the first uptake of ODNs by pollen tubes was reported as early as 1994. A breakthrough in the employment of antisense ODN inhibition as a powerful approach in plant biology was recently presented through our work on intact barley leaves. As was illustrated by confocal microscopy and fluorescently labeled ODNs, naked ODNs were taken up through the leaf petiole and efficiently imported into the plant cell and the nucleus. The work portrayed in that study demonstrate the applicability of antisense ODN inhibition in plant biology, e.g. as a rapid antecedent to time-consuming transgenic studies, and that it operates through RNase H degradation. We employed the antisense ODN strategy to demonstrate the importance of the SUSIBA2 transcription factor in regulation of starch synthesis, and to depict a possible mechanism for sugar signaling in plants and how it might confer endosperm-specific gene expression during seed development. We also described the employment of the antisense ODN strategy for studies on in vitro spike cultures of barley. Here we present further evidence as to the value of the antisense ODN approach in plant biology by following the effects on starch branching enzyme (SBE) accumulation in barley leaves after suppression of individual SBE genes. In agreement with transcript analyses of SBE expression in barley leaves, a zymogram assay (Fig. 1) revealed that sucrose treatment of barley leaves increased the number of SBE activity bands as compared to sorbitol treatment. In the presence of antisense SBEI or SBEIIA ODNs, zymograms of sucrose-treated leaves displayed only a subset of these activities with bands in the top portion of the zymogram gel missing or diminished. With antisense SBEIIB ODN, all activity bands in the top portion of the gel as well as the lowest band were absent. Based on these data we provide a tentative annotation for the various SBE activity bands. In animal experiments, naked ODNs are usually not taken up by the cells since both the ODNs and the outside of the plasma membrane carry a net negative charge. Thus the uptake of naked ODNs into barley leaf cells was surprising and called for an explanation. As demonstrated in our subsequent paper, the answer seems to be that the ODNs slip into the cells through sugar translocators as they are activated in the presence of the appropriate sugar (Fig. 2). Whether it is the structural resemblance between the sugar (deoxyribose) backbone of the ODNs and the transported sugars that allows for the ODNs to be transferred, or if other mechanisms are involved, remains to be elucidated.« less

Especially for High School Teachers

NASA Astrophysics Data System (ADS)

Howell, J. Emory

1999-06-01

Secondary School Feature Article * JCE Classroom Activity #18: Photochemistry and Pinhole Photography: An Interdisciplinary Experiment, by Angeliki A. Rigos and Kevin Salemme, p 736A High School Program at Anaheim ACS Meeting Congratulations to Barbara Sitzman of Chatsworth High School (Los Angeles) and her committee for organizing an outstanding day of activities! With support from the Southern California Section of the American Chemical Society and the encouragement of Tom Wildeman, CHED Program Committee Chair, the program attracted a large number of Southern California teachers and some from much greater distances. A synopsis of some of the day's activities is included in the Chemical Education Program Meeting Report, p 747. Other workshop topics included gel chromatography, forensic chemistry, art preservation and authentication, well water purification, and toxins in waste water. Also, a workshop on fitting polymers into the chemistry course was conducted by the Polymer Ambassadors. I thank Mickey Sarquis, founding editor of the JCE Secondary School Chemistry Section, for joining me in conducting an information workshop. The pictures appearing on this page were taken at the High School/College Interface Luncheon, which featured an address by Paul Boyer. In addition to the opportunity to visit with colleagues, enjoy a meal together, and win door prizes, those in attendance enjoyed a lively hands-on workshop led by Michael Tinnesand, Department Head of K-12 Science, ACS Education Division. Don't you wish you could have attended the High School Program? Plan Now: High School Program in New Orleans Mark your calendar for Sunday, August 22, 1999. The Fall ACS National Meeting will be held in New Orleans and the High School Program is scheduled on Sunday so that teachers will be able to avoid conflicts with the opening of the school year. Teachers in the Mid-South region are especially encouraged to plan on attending an outstanding program put together by Lillie Tucker Akin and her committee. Watch the Journal for program and registration information. Glenn Seaborg Memorial Periodic Table Quilt Raffle Harvey Gendreau of Framingham High School, MA, reports that Barbara McCarty, award-winning quilter and president of the Wayside Quilters Guild, has made a wall-sized periodic table quilt to honor the memory of Glenn Seaborg. The quilt will be raffled at ChemEd99 and funds from the raffle will be used to defray conference costs. The quilt is 2.5 meters wide by 1.5 meters high and the element squares are 13 cm on each side. Each of the 109 element squares contains the appliqué of the symbol and has stenciling for its atomic number and mass. The major periodic families are color coded and the border fabric has an eye-catching symbolic atom design. Nine colors for the elements include royal blue, deep purple, lilac, pink, burgundy and gold. The element square for seaborgium, atomic number 106, has been autographed by Glenn T. Seaborg. A certificate of authenticity will accompany the quilt. This is a unique opportunity to win a classroom (or home) art treasure. Each ticket is 2 or a book of 3 is 5. Tickets may be purchased on the ChemEd99 registration form and will be included in your conference packet. The quilt will be on display at the exposition hall and additional tickets can be purchased at the Unlimited Potential booth. Drawing will be on Wednesday, August 4th, in the expo area when door prizes are announced. You need not be present to win. Information about ChemEd99 may be obtained online at http://www.sacredheart.edu/chemed/. 1999 CMA Catalyst Awards Special congratulations to the High School and Pre-High School award recipients. National Winners are George R. Hague, Dallas, TX, and Wayne Goates, Goddard, KS. Regional winners are Rhonda Lynn Reist, Olathe, KS, and Anne Marie Holbrook, Cincinnati, OH. A complete list of the awardees, including the post-high-school recipients, is in the News & Announcements section of this issue, p 753. NSTA Convention in Boston Thank you to each reader who visited the JCE booth at the NSTA National Convention. With such a large number of exhibits we know that every minute counted and we are glad that you included JCE. We appreciate your suggestions for making JCE more useful to you, as well as hearing about the features of JCE that you like. Highlights from the convention that are of interest to chemistry teachers will be reported next month in this column.

Comparison of ixekizumab with etanercept or placebo in moderate-to-severe psoriasis (UNCOVER-2 and UNCOVER-3): results from two phase 3 randomised trials.

PubMed

Griffiths, Christopher E M; Reich, Kristian; Lebwohl, Mark; van de Kerkhof, Peter; Paul, Carle; Menter, Alan; Cameron, Gregory S; Erickson, Janelle; Zhang, Lu; Secrest, Roberta J; Ball, Susan; Braun, Daniel K; Osuntokun, Olawale O; Heffernan, Michael P; Nickoloff, Brian J; Papp, Kim

2015-08-08

Ixekizumab is a humanised monoclonal antibody against the proinflammatory cytokine interleukin 17A. We report two studies of ixekizumab compared with placebo or etanercept to assess the safety and efficacy of specifically targeting interleukin 17A in patients with widespread moderate-to-severe psoriasis. In two prospective, double-blind, multicentre, phase 3 studies (UNCOVER-2 and UNCOVER-3), eligible patients were aged 18 years or older, had a confirmed diagnosis of chronic plaque psoriasis at least 6 months before baseline (randomisation), 10% or greater body-surface area involvement at both screening and baseline visits, at least a moderate clinical severity as measured by a static physician global assessment (sPGA) score of 3 or more, and a psoriasis area and severity index (PASI) score of 12. Participants were randomly assigned (1:2:2:2) by computer-generated random sequence with an interactive voice response system to receive subcutaneous placebo, etanercept (50 mg twice weekly), or one injection of 80 mg ixekizumab every 2 weeks, or every 4 weeks after a 160 mg starting dose. Blinding was maintained with a double-dummy design. Coprimary efficacy endpoints were proportions of patients achieving sPGA score 0 or 1 and 75% or greater improvement in PASI at week 12. Analysis was by intention to treat. These trials are registered with ClinicalTrials.gov, numbers NCT01597245 and NCT01646177. Between May 30, 2012, and Dec 30, 2013, 1224 patients in UNCOVER-2 were randomly assigned to receive subcutaneous placebo (n=168), etanercept (n=358), or ixekizumab every 2 weeks (n=351) or every 4 weeks (n=347); between Aug 11, 2012, and Feb 27, 2014, 1346 patients in UNCOVER-3 were randomly assigned to receive placebo (n=193), etanercept (n=382), ixekizumab every 2 weeks (n=385), or ixekizumab every 4 weeks (n=386). At week 12, both primary endpoints were met in both studies. For UNCOVER-2 and UNCOVER-3 respectively, in the ixekizumab every 2 weeks group, PASI 75 was achieved by 315 (response rate 89·7%; [effect size 87·4% (97·5% CI 82·9-91·8) vs placebo; 48·1% (41·2-55·0) vs etanercept]) and 336 (87·3%; [80·0% (74·4-85·7) vs placebo; 33·9% (27·0-40·7) vs etanercept]) patients; in the ixekizumab every 4 weeks group, by 269 (77·5%; [75·1% (69·5-80·8) vs placebo; 35·9% (28·2-43·6) vs etanercept]) and 325 (84·2%; [76·9% (71·0-82·8) vs placebo; 30·8% (23·7-37·9) vs etanercept]) patients; in the placebo group, by four (2·4%) and 14 (7·3%) patients; and in the etanercept group by 149 (41·6%) and 204 (53·4%) patients (all p<0·0001 vs placebo or etanercept). In the ixekizumab every 2 weeks group, sPGA 0/1 was achieved by 292 (response rate 83·2%; [effect size 80·8% (97·5% CI 75·6-86·0) vs placebo; 47·2% (39·9-54·4) vs etanercept]) and 310 (80·5%; [73·8% (67·7-79·9) vs placebo; 38·9% (31·7-46·1) vs etanercept]) patients; in the ixekizumab every 4 weeks group by 253 (72·9%; [70·5% (64·6-76·5) vs placebo; 36·9% (29·1-44·7) vs etanercept]) and 291 (75·4%; [68·7% (62·3-75·0) vs placebo; 33·8% (26·3-41·3) vs etanercept]) patients; in the placebo group by four (2·4%) and 13 (6·7%) patients; and in the etanercept group by 129 (36·0%) and 159 (41·6%) patients (all p<0·0001 vs placebo or etanercept). In combined studies, serious adverse events were reported in 14 (1·9%) of 734 patients given ixekizumab every 2 weeks, 14 (1·9%) of 729 given ixekizumab every 4 weeks, seven (1·9%) of 360 given placebo, and 14 (1·9%) of 739 given etanercept; no deaths were noted. Both ixekizumab dose regimens had greater efficacy than placebo and etanercept over 12 weeks in two independent studies. These studies show that selectively neutralising interleukin 17A with a high affinity antibody potentially gives patients with psoriasis a new and effective biological therapy option. Eli Lilly and Co. Copyright © 2015 Elsevier Ltd. All rights reserved.

Cetuximab plus carboplatin and paclitaxel with or without bevacizumab versus carboplatin and paclitaxel with or without bevacizumab in advanced NSCLC (SWOG S0819): a randomised, phase 3 study.

PubMed

Herbst, Roy S; Redman, Mary W; Kim, Edward S; Semrad, Thomas J; Bazhenova, Lyudmila; Masters, Gregory; Oettel, Kurt; Guaglianone, Perry; Reynolds, Christopher; Karnad, Anand; Arnold, Susanne M; Varella-Garcia, Marileila; Moon, James; Mack, Philip C; Blanke, Charles D; Hirsch, Fred R; Kelly, Karen; Gandara, David R

2018-01-01

EGFR antibodies have shown promise in patients with advanced non-small-cell lung cancer (NSCLC), particularly with squamous cell histology. We hypothesised that EGFR copy number by fluorescence in-situ hybridisation (FISH) can identify patients most likely to benefit from these drugs combined with chemotherapy and we aimed to explore the activity of cetuximab with chemotherapy in patients with advanced NSCLC who are EGFR FISH-positive. We did this open-label, phase 3 study (SWOG S0819) at 277 sites in the USA and Mexico. We randomly assigned (1:1) eligible patients with treatment-naive stage IV NSCLC to receive paclitaxel (200 mg/m 2 ; every 21 days) plus carboplatin (area under the curve of 6 by modified Calvert formula; every 21 days) or carboplatin plus paclitaxel and bevacizumab (15 mg/kg; every 21 days), either with cetuximab (250 mg/m 2 weekly after loading dose; cetuximab group) or without (control group), stratified by bevacizumab treatment, smoking status, and M-substage using a dynamic-balancing algorithm. Co-primary endpoints were progression-free survival in patients with EGFR FISH-positive cancer and overall survival in the entire study population. We analysed clinical outcomes with the intention-to-treat principle and analysis of safety outcomes included patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov (number NCT00946712). Between Aug 13, 2009, and May 30, 2014, we randomly assigned 1313 patients to the control group (n=657; 277 with bevacizumab and 380 without bevacizumab in the intention-to-treat population) or the cetuximab group (n=656; 283 with bevacizumab and 373 without bevacizumab in the intention-to-treat population). EGFR FISH was assessable in 976 patients and 400 patients (41%) were EGFR FISH-positive. The median follow-up for patients last known to be alive was 35·2 months (IQR 22·9-39·9). After 194 progression-free survival events in the cetuximab group and 198 in the control group in the EGFR FISH-positive subpopulation, progression-free survival did not differ between treatment groups (hazard ratio [HR] 0·92, 95% CI 0·75-1·12; p=0·40; median 5·4 months [95% CI 4·5-5·7] vs 4·8 months [3·9-5·5]). After 570 deaths in the cetuximab group and 593 in the control group, overall survival did not differ between the treatment groups in the entire study population (HR 0·93, 95% CI 0·83-1·04; p=0·22; median 10·9 months [95% CI 9·5-12·0] vs 9·2 months [8·7-10·3]). In the prespecified analysis of EGFR FISH-positive subpopulation with squamous cell histology, overall survival was significantly longer in the cetuximab group than in the control group (HR 0·58, 95% CI 0·36-0·86; p=0·0071), although progression-free survival did not differ between treatment groups in this subgroup (0·68, 0·46-1·01; p=0·055). Overall survival and progression-free survival did not differ among patients who were EGFR FISH non-positive with squamous cell histology (HR 1·04, 95% CI 0·78-1·40; p=0·77; and 1·02, 0·77-1·36; p=0·88 respectively) or patients with non-squamous histology regardless of EGFR FISH status (for EGFR FISH-positive 0·88, 0·68-1·14; p=0·34; and 0·99, 0·78-1·27; p=0·96; respectively; and for EGFR FISH non-positive 1·00, 0·85-1·17; p=0·97; and 1·03, 0·88-1·20; p=0·69; respectively). The most common grade 3-4 adverse events were decreased neutrophil count (210 [37%] in the cetuximab group vs 158 [25%] in the control group), decreased leucocyte count (103 [16%] vs 74 [20%]), fatigue (81 [13%] vs 74 [20%]), and acne or rash (52 [8%] vs one [<1%]). 59 (9%) patients in the cetuximab group and 31 (5%) patients in the control group had severe adverse events. Deaths related to treatment occurred in 32 (6%) patients in the cetuximab group and 13 (2%) patients in the control group. Although this study did not meet its primary endpoints, prespecified subgroup analyses of patients with EGFR FISH-positive squamous-cell carcinoma cancers are encouraging and support continued evaluation of anti-EGFR antibodies in this subpopulation. National Cancer Institute and Eli Lilly and Company. Copyright © 2018 Elsevier Ltd. All rights reserved.

Especially for High School Teachers

NASA Astrophysics Data System (ADS)

Howell, J. Emory

1999-08-01

Care to Share? An Informal Syllabus Exchange A recent email message from Thomas Shiland, who teaches at Saratoga Springs Senior High School, noted that the process of revising the high school chemistry syllabus is underway in New York State. He expressed a strong interest in helping construct a chemistry syllabus that represents the best thinking about appropriate content. He wondered if it would be possible to develop a way in which different secondary chemistry syllabi could easily be exchanged. It is likely that readers from other states and countries are involved in a similar process and might also be interested in exchanging syllabi. Many states do not use the term syllabus to describe their guiding curricular document for chemistry but rather refer to it as a framework or as guidelines. In most cases, the document includes a list of key ideas or topics, performance indicators, and the major understandings associated with each key idea. Such documents would be appropriate for exchange among those of you involved in the revision process. If you are interested in arranging an exchange please contact me by email at j.e.howell@usm.edu or by mail at J. E. Howell, Box 5043, USM, Hattiesburg, MS39406-5043, USA. High School Day Information The High School Chemistry Program at the American Chemical Society National Meeting in New Orleans, Louisiana will be held Sunday, August 22, 1999, at the Doubletree Hotel, 300 Canal Street. If you wish to register only for the High School Day activities, which includes a pass to the ACS Exposition, a special registration form is available from Lillie Tucker-Akin, 2800 Reynard Dr., Tupelo, MS38801; sci4me@aol.com; fax: 662/566-7906. Advance registration is 25 and the cost of the High School Luncheon is 12. Register in advance by August 1, 1999, or from 7:45 to 8:30 a.m. at the High School Day table in the conference room area of the Doubletree. The workshop schedule is shown below. Secondary School Feature Articles * Exploring the Ocean-Stating the Case for Chemistry, by Paul J. Scheuer, p 1075 * Distillation Apparatuses Using Household Items, by Danielle R. D. Campanizzi, Brenda Mason, Christine K. F. Hermann, p 1079 New Orleans Concurrent Workshops, High School Program 8:30 a.m.-9:20 a.m. A. A Teaching Resource for You: The Journal of Chemical Education, J. E. Howell, J. W. Moore, and A. M. Sarquis B. Electrical Conductivity, J. M. Manion and P. F. Krause, and The Properties of Gases, J.-M. Whitfield and K. A. Woodling C. Chemistry with Calculators for Beginners, P. Sconzo (3 hours) D. Spectrum of Activities for Chemistry Teachers, Carolina Biological Supply, S. Mitchell, F. Cherry, and L. Akin (3 hours) 9:30 a.m.-10:20 a.m. A. Applying Chemical Education Research to the Classroom, L. Akin and J. Valasek B. Another Look at the Deflection of Falling Liquids, H. H. Harris and J. Newstrum, and Encouraging Students to Investigate Acids and Bases Using Plant Indicators, P. K. Kerrigan C. Chemistry with Calculators (continued) D. Spectrum of Activities (continued) E. Science Education for Public Understanding (SEPUP) and Chemistry, Health, Environment, and Me, M. Koker and L. Akin (2 hours) 10:30 a.m.-11:30 a.m. A. Increasing Aptitude and Interest of High School Students through Summer Camp, C. E. Fulton, and Energy Teaching Introduction to High School Chemistry, L.-M. Trejo B. Chemistry in Science Museum Exhibits: Opportunities and Challenges and Cooking with Chemistry, D. Katz C. Chemistry with Calculators (continued) D. Spectrum of Activities (continued) E. SEPUP (continued) 12:00 noon-1:15 p.m., High School Luncheon Educating High School Teachers for the 21st Century, Glenn Crosby 1:30 p.m.-2:20 p.m. A. Customized Mastery Learning in First-Year Chemistry and Computer Software for Chemistry Teachers Who Require Mastery Learning of Their Students, J. Bedenbaugh and A. Bedenbaugh B. Can One Teach Chemistry with Everyday Substances? A. Sae, and SourceBook Activities Using Everyday Substances, C. Ayers, J. Schreck, and M. V. Orna C. Chemistry with Calculators II, P. Sconzo (3 hours) D. An Enlightening Afternoon of Lab Safety, Carolina Biological Supply, J. Kaufman E. Alabama Science in Motion, T. Boman and C. Nassar (90 minutes) 2:30 p.m.-3:20 p.m. A. An Activity to Show Chemistry Students How to Organize Experimentally Determined Information and Using Chemistry to Teach Reasoning Skills, A. Bedenbaugh B. Demonstrations with Gases, M. D. Alexander, and The Ring of Fire with Rubbing Alcohol and a Couple of Others, W. Deese C. Chemistry with Calculators II (continued) D. An Enlightening Afternoon of Lab Safety (continued) E. Alabama Science in Motion (continued) and Buck Scientific, J. DeMenna 3:30 p.m.-4:30 p.m. A. How Flawed Textbook Experiment Can Lead to an Opportunity for Guided Discovery by Students and a Simpler, Better Experiment, J. Bedenbaugh B. Demonstrating Applications of Chemistry with Everyday Substances, D. Katz C. Chemistry with Calculators II (continued) D. An Enlightening Afternoon of Lab Safety (continued) E. Buck Scientific (continued)

Especially for High School Teachers

NASA Astrophysics Data System (ADS)

Emory Howell, J.

1999-11-01

More Feature Articles This Month This issue contains a larger-than-usual number of Secondary School Chemistry feature articles (see side-bar). Mary Harris, who teaches in St. Louis, Missouri, and her student, Lauren Picard, contributed an account of student research on the cuprammonium rayon process (p 1512). In addition to being informative and interesting, the article provides a model for student-teacher interaction in carrying out an independent research project. Two North Carolina teachers, Charles Roser and Catherine McCluskey, describe how to use a Calculator Based Laboratory (interface) to measure the kinetics of the reaction that occurs when a lightstick is activated (p 1514). The method and the easy-to-construct device they made could be used with other systems, as well. Don't Throw Away the Carrier Sheet All areas of JCE Online are now accessible to all JCE subscribers. To find out how you can benefit, read the article appearing on p 1599, Now That I Have It, What Can I Do with It? Jon Holmes, Editor of JCE Online, explains in the article how you can use this resource most effectively. Access to several areas, such as full text access to articles, requires that you log in. The mailing label on the carrier sheet that accompanies your Journal each month contains a password that you need to log in. That is why you need to keep the carrier sheet, at least until you have logged in for the first time and either memorized the number or written it in a safe place. Detailed instructions for logging on are found by clicking on the "How to Log On" link, which appears near the upper left corner of the JCE Online Home Page, jchemed.chem.wisc.edu. If you read a school library copy you need to ask your librarian what password you need to log in. Congratulations Among the recipients of the most prestigious American Society Awards (p 1481) are two individuals who have given generously of their time and energy to the cause of chemical education. Both are familiar names to many of our readers. The High School/College Interface Luncheon was part of the very rich day-long High School Program at the New Orleans ACS Meeting. Shown here (from left) are Glenn Crosby, the luncheon speaker; Lillie Tucker-Akin, the High School Day program chair; and Fred Johnson, Assistant Superintendent of Shelby County (TN) schools and Immediate Past President of NSTA. The recipient of the James Bryant Conant Award in High School Chemistry Teaching is Frank G. Cardulla, who taught for many years at Niles North High School, Skokie, Illinois. His extensive record of service to fellow teachers includes editing the JCE "View from My Classroom" feature for several years and writing several articles, as well as his recent appointment to the JCE Board of Publication. The recipient of the George C. Pimentel Award in Chemical Education is Jerry A. Bell of the American Chemical Society in Washington, DC. An author of numerous articles appearing in JCE and a member of the JCE Board of Publication for several years, he currently serves as Board Chair. The 16th Biennial Conference on Chemical Education Readers who attended the 15th BCCE in Waterloo, Ontario, know that much of the programming at these conferences is of interest to high school teachers. Many work shops, papers, and demonstrations are presented by high school teachers. There are many other outstanding papers and posters, plenary speakers, and exciting demonstrations. The 16th BCCE will be held at the University of Michigan in Ann Arbor, July 30-August 3, 2000. Among the high school teachers already scheduled to present workshops at the 16th BCCE are George Hague, Lynn Hershey, and Jack Randall, and there will be many more before the program is completed. The High School Chemistry Program Chair is Tim Graham, Roosevelt High School (MI). The Organizing Committee is seeking the assistance of local sections of the American Chemical Society within a 300-mile radius of Ann Arbor in providing support for high school teachers to attend the conference. High school teachers who wish to attend, whether within the 300-mile radius or beyond, are encouraged to contact their local section of the ACS. Information about local sections can be found on the Web at www.acs.org. See p 1482 for more information about the conference, including deadlines for proposals and abstracts and for the conference Web site address. Secondary School Feature Articles * The Chemistry of Modern Dental Filling Materials, by John W. Nicholson and H. Mary Anstice, p 1497 * JCE Classroom Activity #21: Hunting for Chemicals in Consumer Products, p 1504A, by Arthur M. Last * Science for Kids Outreach Programs, by Birgit G. Koehler, Lee Y. Park, and Lawrence J. Kaplan, p 1505 *Henry's Law and Noisy Knuckles by Doris R. Kimbrough, p 1509 *Investigating the Cuprammonium Rayon Process in a High School Laboratory, by Lauren J. Pickard and Mary E. Harris, p 1512 * Lightstick Kinetics, by Charles E. Roser and Catherine L. McCluskey, p 1514

Dulaglutide versus insulin glargine in patients with type 2 diabetes and moderate-to-severe chronic kidney disease (AWARD-7): a multicentre, open-label, randomised trial.

PubMed

Tuttle, Katherine R; Lakshmanan, Mark C; Rayner, Brian; Busch, Robert S; Zimmermann, Alan G; Woodward, D Bradley; Botros, Fady T

2018-06-14

Many antihyperglycaemic drugs, including insulin, are primarily cleared by the kidneys, restricting treatment options for patients with kidney disease. Dulaglutide is a long-acting glucagon-like peptide-1 receptor agonist that is not cleared by the kidneys, and confers a lower risk of hypoglycaemia than does insulin. We assessed the efficacy and safety of dulaglutide in patients with type 2 diabetes and moderate-to-severe chronic kidney disease. AWARD-7 was a multicentre, open-label trial done at 99 sites in nine countries. Eligible patients were adults with type 2 diabetes and moderate-to-severe chronic kidney disease (stages 3-4), with an HbA 1c of 7·5-10·5%, and who were being treated with insulin or insulin plus an oral antihyperglycaemic drug and were taking a maximum tolerated dose of an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker. Participants were randomly assigned (1:1:1) by use of a computer-generated random sequence with an interactive response system to once-weekly injectable dulaglutide 1·5 mg, once-weekly dulaglutide 0·75 mg, or daily insulin glargine as basal therapy, all in combination with insulin lispro, for 52 weeks. Insulin glargine and lispro doses were titrated as per an adjustment algorithm; dulaglutide doses were masked to participants and investigators. The primary outcome was HbA 1c at 26 weeks, with a 0·4% non-inferiority margin. Secondary outcomes included estimated glomerular filtration rate (eGFR) and urine albumin-to-creatinine ratio (UACR). The primary analysis population was all randomly assigned patients who received at least one dose of study treatment and had at least one post-randomisation HbA 1c measurement. The safety population was all patients who received at least one dose of study treatment and had any post-dose data. This study is registered with ClinicalTrials.gov, number NCT01621178. Between Aug 15, 2012, and Nov 30, 2015, 577 patients were randomly assigned, 193 to dulaglutide 1·5 mg, 190 to dulaglutide 0·75 mg, and 194 to insulin glargine. The effects on HbA 1c change at 26 weeks of dulaglutide 1·5 mg and 0·75 mg were non-inferior to those of insulin glargine (least squares mean [LSM] -1·2% [SE 0·1] with dulaglutide 1·5 mg [183 patients]; -1·1% [0·1] with dulaglutide 0·75 mg [180 patients]; -1·1% [0·1] with insulin glargine [186 patients]; one-sided p≤0·0001 for both dulaglutide doses vs insulin glargine). The differences in HbA 1c concentration at 26 weeks between dulaglutide and insulin glargine treatments were LSM difference -0·05% (95% CI -0·26 to 0·15, p<0·0001) with dulaglutide 1·5 mg and 0·02% (-0·18 to -0·22, p=0·0001) with dulaglutide 0·75 mg. HbA 1c -lowering effects persisted to 52 weeks (LSM -1·1% [SE 0·1] with dulaglutide 1·5 mg; -1·1% [0·1] with dulaglutide 0·75 mg; -1·0% [0·1] with insulin glargine). At 52 weeks, eGFR was higher with dulaglutide 1·5 mg (Chronic Kidney Disease Epidemiology Collaboration equation by cystatin C geometric LSM 34·0 mL/min per 1·73 m 2 [SE 0·7]; p=0·005 vs insulin glargine) and dulaglutide 0·75 mg (33·8 mL/min per 1·73 m 2 [0·7]; p=0·009 vs insulin glargine) than with insulin glargine (31·3 mL/min per 1·73 m 2 [0·7]). At 52 weeks, the effects of dulaglutide 1·5 mg and 0·75 mg on UACR reduction were not significantly different from that of insulin glargine (LSM -22·5% [95% CI -35·1 to -7·5] with dulaglutide 1·5 mg; -20·1% [-33·1 to -4·6] with dulaglutide 0·75 mg; -13·0% [-27·1 to 3·9] with insulin glargine). Proportions of patients with any serious adverse events were similar across groups (20% [38 of 192] with dulaglutide 1·5 mg, 24% [45 of 190] with dulaglutide 0·75 mg, and 27% [52 of 194] with insulin glargine). Dulaglutide was associated with higher rates of nausea (20% [38 of 192] with dulaglutide 1·5 mg and 14% [27 of 190] with 0·75 mg, vs 5% [nine of 194] with insulin glargine) and diarrhoea (17% [33 of 192] with dulaglutide 1·5 mg and 16% [30 of 190] with 0·75 mg, vs 7% [14 of 194] with insulin glargine) and lower rates of symptomatic hypoglycaemia (4·4 events per patient per year with dulaglutide 1·5 mg and 4·3 with dulaglutide 0·75 mg, vs 9·6 with insulin glargine). End-stage renal disease occurred in 38 participants: eight (4%) of 192 with dulaglutide 1·5 mg, 14 (7%) of 190 with dulaglutide 0·75 mg, and 16 (8%) of 194 with insulin glargine. In patients with type 2 diabetes and moderate-to-severe chronic kidney disease, once-weekly dulaglutide produced glycaemic control similar to that achieved with insulin glargine, with reduced decline in eGFR. Dulaglutide seems to be safe to use to achieve glycaemic control in patients with moderate-to-severe chronic kidney disease. Eli Lilly and Company. Copyright © 2018 Elsevier Ltd. All rights reserved.

[A 50-year history of new drugs in Japan-the development and progress of anti-diabetic drugs and the epidemiological aspects of diabetes mellitus].

PubMed

Ozawa, Hikaru; Murai, Yuriko; Ozawa, Terutaka

2003-01-01

The development and progress of antidiabetic drugs (e.g., insulin preparations and hypoglycemic drugs) are retrospectively investigated in Japan. Their influences on the treatment of diabetes mellitus (DM) and its epidemiological aspects are also discussed. 1) Insulin preparations: Insulin was introduced for DM therapy in 1925, two or three years after its discovery in Canada. The preparations were raw extracts of bovine or porcine pancreas. These did not prevail widely in Japan because of the low incidence of DM before World Wan II. After the war, a shortage of mammalian materials compelled the use of fish pancreatic tissues such as bonito and/or tuna for insulin production. Insulin infection, so-called regular insulin, was first promoted in the 6th "Pharmacopoeia Japonica" (JP6) in 1951 and has been maintained to the present edition (JP14, 2001). Although depot-type insulin preparations were developed in the USA and Europe during the war, the introduction of those preparations to Japan was delayed until 1951, when Protamine zinc insulin appeared. Globin zinc insulin and Isophane insulin were introduced for clinical use in 1952 and 1955, respectively. These were also adopted for JP7 (1961). Biphasic-type insulin, which has a rapid onset and long duration of activity, appeared in 1965. Purified preparations from bovine or porcine sources have been available since 1980, which might be a strong reason for the decrease in insulin allergy. Insulin from animal origin has been supplied for almost 60 years since its discovery. Amino acid sequences of insulins from various species of animals were determined by the pioneering studies of Sanger and his associates. Human insulin, which differs from porcine insulin by only one amino acid, was produced by Novo researchers in 1982 using a semi-synthetic method. Then the Lilly group soon succeeded in obtaining human insulin by recombinant DNA technology in the same year. Both products were introduced to Japan in 1985, and the recombinant products prevailed throughout the 1990s. Human insulin analogues (i.e., Insulin lispro and Insulin aspart) appeared in 2001. These are applied for after-meal glycosmia owing to their ultrarapid onset of activity. Self-injection by DM patients was legalized in 1981. To make the infection technique sure and easy, cartridge (pen-type) and disposable kit-type needles were devised in the 1990s. 2) Oral hypoglycemic drugs: Instead of the exclusive parenteral usage of insulins, there was also demand for oral dosage forms. The first of the sulfonyrlurea (SU) group, BZ-55, was used for DM clinically in 1955 in Germany. But it was soon withdrawn because of its antibacterial action. This led to the development of various SU groups. Tolbutamide (1956), chlorpropamide (1959), acetohexamide (1964) and tolazamide (1961) were introduced to Japan as first-generation SUs. Then glyclopyramide (Kyorin, 1965), glybenclamide (1971), gliclazide (1984) and glimepiride (1999) appeared as the second-generation SUs. These were used orally for Type 2 diabetes. Biguanide (BG) group, phenformin HC1 (1959), metformin HC1 (1961) and buformin HC1 (1961) had also been in use by oral treatment of Type 2 diabetes. SU appears to act by increasing the sensitivity of b-cells, which secrete insulin. BG probably exerts by increasing glucose transport across the membranes of target organs. 3) New types of antidiabetic drugs: a-Glucosidase inhibitors (i.e., acarbose: Bayer, 1993; and voglibose: Takeda, 1994) act on hyperglycemia after meals by decreasing glucose absorption. Thiazolidinedione compounds, such as troglitazone (Sankyo, 1995) and pioglitazone HC1 (Takeda, 1994) act by increasing the insulin sensitivity of the target tissues. These are useful for Type 2 DM patients when SUs are ineffective. Nevertheless, troglitazone was discontinued in 2000 due to severe liver damage. Nateglinide (Ajinomoto Co., 1999), which is a D-phenylalanine derivative acting similar to SUs, is useful orally for after-meal hyperglycemia of Type 2 diabetes. Epalrestat (Ono Yakuhin Co., 1992) is effective for diabetic neuropathy by reducing the formation of sorbitol. These anti-DM drugs were recently studied and developed in Japan. 4) The Japan Diabetes Society proposed a guideline on diagnostic criteria and treatment of diabetes mellitus (DM) in 1999 and revised it in 2002. DM is classified as insulin-dependent DM (Type l) and non-insulin dependent DM (Type 2). Type 1, juvenile onset DM, requires insulin therapy to prevent ketosis and to sustain life. Treatment of type 2, adult onset DM, is recommended as a step-by-step method, starting with dietary-exercise therapy, followed by oral hypoglycemic drugs and then insulin therapy. DM patients with complications should have a therapy devised to match their circumstances. 5) Epidemiological aspects: The mortality rate of DM compared to the time of drug appearance was traced from 1920 to 2000. The curve goes down slowly in the time frame of World War II, but rises from 1950 to 1970. The elevation could not be suppressed by the appearance of SUs, BGs or improved insulin preparations. The curve runs flat from 1980 to 1990, which might be related to the use of purified insulin or human insulin therapy. The mortality rate of DM indicates that death by hyperglycemic coma and other deaths resulting from complications are excluded. The survey of the principal cause of death by DM during the period of 1981-1990 indicates that the death rate due to hyperglycemic coma is only 1.7% of the total deaths caused by DM. The effect of drug therapy on all of the death resulting from DM is not detected. Hospital visitation and admission rates of the DM patients have been recorded since 1952 in Japan. This curve is rising continuously, and none of the antidiabetic drugs has been able to suppress it. These data show that the antidiabetic drugs relieve DM symptoms through their effective hypoglycemic actions, but that they cannot suppress the mortality rate of DM. It is possible that none of the drugs currently available can suppress the increasing tendency of DM patients.

NACA Aircraft in hangar 1953 - clockwise from front center: YF-84A, D-558-1, D-558-2, B-47, X-1 ship

NASA Technical Reports Server (NTRS)

1953-01-01

In the center foreground of this 1953 hanger photo is the YF-84A (NACA 134/Air Force 45-59490) used for vortex generator research. It arrived on November 28, 1949, and departed on April 21, 1954. Beside it is the third D-558-1 aircraft (NACA 142/Navy 37972). This aircraft was used for a total of 78 transonic research flights from April 1949 to June 1954. It replaced the second D-558-1, lost in the crash which killed Howard Lilly. Just visible on the left edge is the nose of the first D-558-2 (NACA 143/Navy 37973). Douglas turned the aircraft over to NACA on August 31, 1951, after the contractor had completed its initial test flights. NACA only made a single flight with the aircraft, on September 17, 1956, before the program was cancelled. In the center of the photo is the B-47A (NACA 150/Air Force 49-1900). The B-47 jet bomber, with its thin, swept-back wings, and six podded engines, represented the state of the art in aircraft design in the early 1950s. The aircraft undertook a number of research activities between May 1953 and its 78th and final research flight on November 22, 1957. The tests showed that the aircraft had a buffeting problem at speeds above Mach 0.8. Among the pilots who flew the B-47 were later X-15 pilots Joe Walker, A. Scott Crossfield, John B. McKay, and Neil A. Armstrong. On the right side of the B-47 is NACA's X-1 (Air Force 46-063). The second XS-1 aircraft built, it was fitted with a thicker wing than that on the first aircraft, which had exceeded Mach 1 on October 14, 1947. Flight research by NACA pilots indicated that this thicker wing produced 30 percent more drag at transonic speeds compared to the thinner wing on the first X-1. After a final flight on October 23, 1951, the aircraft was grounded due to the possibility of fatigue failure of the nitrogen spheres used to pressurize the fuel tanks. At the time of this photo, in 1953, the aircraft was in storage. In 1955, the aircraft was extensively modified, becoming the X-1E. In front of the X-1 is the XF-92A (Air Force 46-682). Unlike the X-1 and D-558 aircraft, the XF-92A was not designed as a research aircraft, but as the prototype of a delta-wing fighter. While the effort was unsuccessful, the XF-92A offered the chance to test a delta wing aircraft. A brief series of 25 flights were made using the aircraft in 1953. These showed the aircraft had violent pitch-up tendencies during turns. Despite the problems, the XF-92A contributed to later delta wing aircraft, like the F-102, F-106, and B-58. Behind the B-47, in the back of the hangar, are four other aircraft. From left to right, they are the second X-4 (Air Force 46-677) research aircraft. It was operated by the NACA from May 8, 1950, to March 22, 1954, when it left the High-Speed Flight Research Station for the U.S. Air Force Museum. It was designed to test the use of swept wings but no horizontal stabilizers. This proved to have poor transonic stability. Next to it is the ETF-51D Mustang (NACA 148/Air Force 44-84958) used for low-speed chase missions, as well as support and liaison flights. On the right side of the B-47 is the first D-558-1. Originally given the Navy number 37970, it was flown as part of the Douglas contractor program. When this was completed, the aircraft was turned over to the NACA on April 11, 1949. Although the aircraft was designation 'NACA 140,' it was never flown again. Instead, it was used to provide spare parts to keep the third D-558-1 in operation. In this photo the aircraft is partially disassembled. The final aircraft is the first X-5 (Air Force 50-1838). This was a research aircraft used to test the concept of pivoting wings which could change their sweep angle in flight. The results were mixed; the X-5 had vicious stall behavior due to the poor position of the tail and stabilizers. The mechanism used by the 'variable-sweep wing' was also complex, which limited its usefulness. Despite these problems, the X-5's primary advantage was that it was equivalent to a whole family of research aircraft. It could provide transonic data at sweep angles up to 60 degrees--the same as the delta wing XF-92A. The Dryden Flight Research Center, NASA's premier installation for aeronautical flight research, celebrated its 50th anniversary in 1996. Dryden is the 'Center of Excellence' for atmospheric flight operations. The Center's charter is to research, develop, verify, and transfer advanced aeronautics, space, and related technologies. It is located at Edwards, Calif., on the western edge of the Mojave Desert, 80 miles north of Los Angeles. Dryden's history dates back to the early fall of 1946, when a group of five aeronautical engineers arrived at what is now Edwards from the NACA's Langley Memorial Aeronautical Laboratory, Hampton, Va. Their goal was to prepare for the X-l supersonic research flights in a joint NACA-U.S. Army Air Forces-Bell Aircraft Corp. program. NACA--the National Advisory Committee for Aeronautics--was the predecessor of today's NASA. Since the days of the X-l, the first aircraft to fly faster than the speed of sound, the installation has grown in size and significance and is associated with many important developments in aviation -- supersonic and hypersonic flight, wingless lifting bodies, digital fly-by-wire, supercritical and forward-swept wings, and the space shuttles. Its name has changed many times over the years. From 14 November 1949 to 1 July 1954 it bore the name NACA High-Speed Flight Research Station.

Tarasca: ritual monster of Spain.

PubMed

Gilmore, David D

2008-09-01

Let us now revisit our original assumptions. First, we note that for the participants in Hacinas Carnival the Tarasca is a figure of fun and joy, but it also exudes a strain of aggressive misogyny that many female residents, not to mention tourists, find somewhat unsettling. In the spirit of feminist currents in Spain, a group of young women protested in 1992 to town officials and, when rebuffed, sought to build their own female monster, which they intended to use to attack boys and men. While their plan was never carried out, and indeed met with stiff opposition from officialdom and, especially, from older women, some of the younger, more modern girls find the Tarasca appalling, and they told me so without compunction. Accordingly, today the festival tends to polarize the sexes as well as the generations. Also, many children are frightened by the gigantic mock-up with its snapping teeth and foul breath, and many of them burst into tears at the roaring of the demons. But despite these negatives--or perhaps because of them--the Tarasca breaks down boundaries between things normally kept separate in the mind: humor and terror, man and beast, order and disorder, old and young, life and death, and so on. In so collapsing opposites, the Tarasca causes people to pause and to think about and question everyday reality in the non-Carnival universe. All these observations of course support the structural arguments of our four theorists above and in particular seem to corroborate Bloch's concept (1992) of the regenerative power of "rebounding violence." However, there are three specific features here that need psychological amplification beyond simply confirming the work of previous theorists. We must first note that like most grotesque fantasies, the Hacinas monster combines disparate organic "realities" into a bizarre and monstrous image that by its very oddness and the resulting "cognitive mismatch" captures people's attention and sparks the imagination, especially that of children (Konner 2002, 222). The Pentecostal beastie combines equine, reptilian, and bird-like features with a giraffe's neck, an elephant's bulk, an impossible number of legs, the usual human malevolence, and the satyr's insatiable lust. The monster also combines cognitive antitheses in a way that reinforces cultural biases while at the same time undermining them--a typical paradox of the Monstrous in ritual and art (Andriano 1999). In the Hacinas festival the integrated themes are those of bodily mutilation, sexual abuse, cannibalism, death, and decay. All these themes come together in certain compelling Iberian traditions: misogyny, costumed parading, religious revitalization, ritual displacement of aggression onto external objects, spontaneous street theatre. All forms of aggression are visually embodied in the image of the mystic beast, as happens every day in the classic Spanish bullfight pitting man against raw nature (Mitchell 1991). Peremptory male sexuality both parodied and glorified, women both raped and rescued, children both terrified and liberated. As Bloch has argued in the aptly titled Prey into Hunter (1992), the narrative of the Tarasca rite, turning victim into victimizer, enables the community to "absorb the vitality" of the external threat and thereby to regenerate itself and to transcend everyday reality. We may make a third, psychoanalytic, observation. As with all such fabulous and scary images, the Tarasca provokes regressive responses that probably go back to the primary organization of the mind before the advent of speech. In this childhood environment, sensations are limited to visions and primary emotions, and the world is experienced largely through the eyes and mouth. Psychoanalysts of childhood have called this the phase of oral/visual primacy. It may explain the locus of aggression in typical monster imagery: the rending teeth, the gnashing jaws, the cavernous belly. It would also help us understand the terror at being devoured by a giant predator during the ritual or, as Bloch puts it (1992, 101), "the horrifying possibility of being consumed" as an essential aspect of ritual process. The snapping mouth as well as other incorporative morphological features of the Hacinas monster, for example, the bulging belly, give an animated shape to primordial fear, with its dynamic mixture of oral, erotic, and self-identity themes. This is exactly what Bloch refers to as the "consuming" threat, the evil that "bites" and "eats" before succumbing to the power of the good. The Tarasca exemplifies both childhood anxieties and the residual fears of adults; and so the festival evokes passionate intensity in all age groups. As Turner might have put it, the "pressure points" that find expression in Hacinas are those between sexual desire and guilt, terror and curiosity, good and evil, purity and corruption; the tensions are those between old and young, death and re-birth (emerging anew from the Tarasca's belly). All of these themes are probably universally encountered and thus constitute the "core" of rituals everywhere by "reenacting the creation ot moral life" (Bloch 1992, 47). Although the Tarasca frightens children and makes them bawl and run away, it also stimulates their cognitive growth and offers ultimately a sense of safety provided by a united and victorious community. Some child psychologists such as Denyse Beaudet (1990) and Jean Piaget (1962, 229) have surmised as much. Piaget says that unconstrained mental operations caused by shock or disorientation provide Spieltaum: an imaginary playground where youngsters experiment with ideas. Bruno Bettelheim says that such creativity permits children to give anxieties tangible form: these can then be distanced and defeated (1976, 120). This projective process, beginning in infancy, of course continues in adulthood, not only in dreams and fantasy but in community rituals, where it reaches apotheosis as Bloch has so persuasively argued. Finally, we must address the misogynist theme that is so marked in the Spanish festival. Many anthroooloeists have noted the theme of the treacherous siren in Spanish folklore, a theme that corresponds to the female models carried aloft on the Tarasca's spine in Granada, Toledo, and other places. One observer, Stanley Brandes, was impressed with the pervasiveness of this specific male anxiety in the Andalusian town of Monteros. In his book on male folklore, Metaphors of Masculinity (1980), Brandes records a number of popular aphorisms that warn men to protect their fragile manhood from duplicitous females or suffer emasculation (one urges men literally to keep their penises in their pants or be castrated). In my own fieldwork in Seville Province, I found the eating/castration theme paramount in male folklore and I have recorded numerous Carnival ditties warning men and boys against the vagina dentata and other forms of female sexual aggression (Gilmore 1987; 1998). Literary scholar Louise Vasvari (1991, 3) refers to the "gastro-genital equivalence" symbolism of Spanish versification, which she identifies in writings dating back to the Middle Ages. Given all this evidence, we may conclude that with its defining misogynist theme and its female/monster imagery, the Spanish Tarasca embodies a dread of feminine sexuality that colors the Spanish male subculture. In particular, in the Hacinas case, the misogynist element combines a devouring theme along with the castration threat in the attack on the boys' genitals and in the liquid thrown onto the crotch, symbolizing, one may conjecture, semen and blood. While these themes are probably universal, their annual apotheosis in visual tropes, public rites, monster effigies, and masques may be specific to Spain. Both appalling in its ferocity and ennobling in its ultimate function as sacrificial object, the Tarasca is one of countless projections of universal human mental shadows as an embodiment, a visual metaphor, as James Fernandez has shown in his classic paper on the role of tropes in culture (1986). Like the other monsters of the world, the Tarascas of Spain are man-eaters and rapists, both lascivious females and priapic males; their toothy (and in Hacinas smelly) oral symbolism is at the same time lurid and hypnotic to the crowds that fight them. As an aspect of local pride, the beast calls forth reverence as well as repugnance. Frightening and also endearing, the Tarasca embodies the human imagination in all its whimsy, grotesqueness, and terror.

New ways of insulin delivery.

PubMed

Heinemann, L

2011-02-01

The predominant number of papers published from the middle of 2009 to the middle of 2010 about alternative routes of insulin administration (ARIA) were still about inhaled insulin. Long-term experience with Exubera was the topic of a number of publications that are also of relevance for inhaled insulin in general. The clinical trials performed with AIR insulin by Eli Lilly were published in a supplement issue of one diabetes technology journal and most of these will be presented. A number of other publications (also one in a high ranked journal) about their inhaled insulin were from another company: MannKind. The driving force behind Technosphere insulin (TI) - which is the only one still in clinical development - is Al Mann; he has put a lot of his personal fortune in this development. We will know the opinion of the regulatory authorities about TI in the near future; however, I am personally relatively confident that the Food and Drug Administration will provide TI with market approval. The more critical question for me is: will diabetologists and patients jump on this product once it becomes commercially available? Will it become a commercial success? In view of many negative feelings in the scientific community about inhaled insulin, it might be of help that MannKind publish their studies with TI systematically. Acknowledging being a believer in this route of insulin administration myself, one has to state that Exubera and AIR insulin had not offered profound advantages in terms of pharmacokinetic (PK) and pharmacodynamic (PD) properties in comparison with subcutaneously (SC) applied regular human insulin (RHI) and rapid-acting insulin analogues. The time-action profiles of these inhaled insulins were more or less comparable with that of rapid-acting insulin analogues. This is clearly different with TI which exhibits a strong metabolic effect shortly after application and a rapid decline in the metabolic effect thereafter; probably the duration of action is even too short (see postprandial glycaemic excursions with test meals in the publication by Rosenstock et al. in The Lancet (1)). In the end a number of aspects are of relevance for the success of a given product; one key aspect is clearly the price. However, for patients also practical aspects (handling, need for regular pulmonary function test etc.) are of importance. We shall have to see how creatively MannKind will handle all such questions. Until now Al Mann and his colleagues were able to manage a number of challenges during the clinical development process successfully, so one can have hopes for the market success of TI. However, it is clear that at the same time, if TI fails like Exubera did before, this will be the end for pulmonary insulin in general. Not too many original publications presenting data from clinical trials were published in the last year when it comes to oral insulin (OI), nasal insulin or transdermal insulin developments; simply none with transdermal insulin. Also at the last international congresses not many studies about ARIA were presented. At least in part this might be still a reflection of the shockwaves that the failure of Exubera has sent out to pharmaceutical companies and venture capitalists; they are quite reluctant to invest in any of these developments. However, a considerable number of reviews (in some cases more than original papers!) were published about ARIA. These reviews are listed for completeness, but in most cases are not further commented. OI is still the area of research most companies are active in; however, in some cases it is not clear how active they really are (e.g. Diabetology). Nevertheless, at least some companies are quite active and progressed in their clinical development programme close to market approval, e.g. the large Indian company Biocon is in late phase 3 with IN-105 and the small Israel-based company Oramed is in phase 2b. It appears that other interesting OI developments (e.g. Diasome) were not very active in the last year; at least they have not published new study results. It is clear that for companies that produce insulin themselves (e.g. Biocon) the costs of the good are not of such relevance as for companies that have to buy it commercially. For the latter ones a low bioavailability/biopotency compared with SC insulin administration can be a real hurdle when it comes to the price of their product. Despite some publications about nasal insulin, the overall activity with this route of insulin administration appears to be low; the same holds true for transdermal insulin. Insulin pens have gained more scientific interest in recent years, which is also reflected by an increase in publications, starting from practically nil 10 years ago to a solid number of five to 10 papers per year nowadays. Besides ARIA there are also attempts to increase the speed of insulin absorption after injection into the skin by applying it not into the SC tissue but intradermally or by heating up the skin above the SC insulin depot. Reading a number of papers that were not included in this chapter because they do not present any clinical data but are novel developments tested only in animal experiments so far, the clear message is that there is definitely not a lack of creativity/imagination amongst scientists; each year a plethora of new ideas for insulin application show up. Unfortunately not too many make it towards a full clinical development. As long as there is not a single successful product on the market that is based on a given ARIA approach, this area of research will not mature. For many patients, avoiding the need for SC injections is attractive; however, as long as no clear 'advantage' can be demonstrated, reimbursement will be difficult to achieve. Living in the time of evidence-based medicine it is clear that 'relevant' clinical advantages must be proven. The question is what is relevant. Is it just an improvement in metabolic control (= decrease in HbA1c)? Can this also mean that more patients are willing to start insulin therapy earlier than with conventional SC insulin therapy? With TI we have a product that has improved pharmacological properties (also in comparison to Exubera) for coverage of prandial insulin requirements. Subsequently, in the clinical trials performed, postprandial glycaemic excursions were lower than with SC injection of RHI or rapid-acting insulin analogues. This only in part (if at all) results in an improved metabolic control in general (= lower HbA1c) (see below). The outlook for 2011 is that there are chances that we shall have an inhaled insulin product on the market. Probably also the first OI will be submitted to the regulatory authorities for market approval or will even be available in less regulated markets. In order to select all relevant publications about new ways of insulin delivery I performed a PUBMED search and also checked the table of contents of a number of journals that publish heavily in this area of research as well references in the publications I found for additional references. Selection of the manuscripts from all publications was predominately based on the fact whether they presented data from clinical studies or not. The selected studies were critically reviewed for novelty and appropriate study design etc. In some cases also reviews about a given topic were selected if they provide relevant novel insights. © 2011 Blackwell Publishing Ltd.

Obituary: Gary Lars Grasdalen, 1945-2003

NASA Astrophysics Data System (ADS)

Strom, Stephen Eric

2003-12-01

With the passing of Gary Grasdalen on 20 April 2003 the astronomical community has lost one its most creative members. Born in Albert Lea, Minnesota on 7 October 1945 to the farming family of Lars G. and Lillie Grasdalen, Gary developed a strong childhood interest in science, and a particular fascination with astronomy. In 1964, he entered Harvard College intending to pursue those interests. During his freshman year, Gary enrolled in an undergraduate research seminar in which he first displayed the combination of keen insight and imagination in applying new techniques that was manifest throughout his professional career. In 1968, he published his first two papers---studies of the C12/C13 ratio in metal deficient stars, and of Fe I and Fe II transition probabilities---which summarized research carried out during his junior and senior years at Harvard. Grasdalen next entered the astronomy graduate program at the University of California, Berkeley. There he developed a strong interest in the early stages of stellar evolution and, in particular, the potential of S-1 image intensifiers and newly available near-infrared detectors to detect and analyze the stellar populations embedded within their parent molecular cloud complexes. Following award of his PhD in 1972, Grasdalen was appointed to the staff at the Kitt Peak National Observatory. Early in his career at KPNO, Gary developed tools that enabled routine near-infrared mapping of nearby molecular cloud complexes, most notably the telescope control programs that enabled precise raster scanning of these regions. Those same programs were some of the many innovations in which Gary had a hand. These innovations enabled a generation of KPNO observers in the 1970s to fully exploit the power of the newly commissioned Mayall telescope as well as the smaller telescopes on Kitt Peak. In 1973, he published the first map of the central region of a molecular cloud, which revealed an extensive embedded, optically obscured population of newly formed stars in the Ophiuchus complex. This discovery led to a series of survey papers cataloging and describing the young stellar population associated with multiple nearby clouds. The results from these early survey papers produced finding lists and nomenclature for embedded young stars that are still referenced by researchers. By developing the tools needed to point telescopes precisely, Grasdalen was able to follow a hunch that he had while a graduate student at Berkeley---that Herbig-Haro objects were excited by optically obscured young stars that were displaced from these emission nebulae. He believed these objects to be reflection nebulae, scattering light earthward from a young star whose powerful wind had carved out a cavity thus creating an indirect pathway for optical photons to reach observers from an otherwise invisible star. Grasdalen compiled a list of candidate H-H objects from the Palomar Observatory Sky Survey and began a near-infrared search for associated young stars, first using inefficient PbS and when they became available, InSb detectors. In 1974, his insight was rewarded with the discovery of the embedded young star associated with H-H 100 in Corona Austrina, and soon thereafter, with multiple candidate infrared sources associated with H-H objects. The 1974 discovery paper notes that the exciting source for H-H 100 is located near the geometric center of a 0.1 pc, roughly spherical cloud, providing early evidence that young stars form within regions that we now call ``molecular cores". Following several years of study, it became clear that the H-H objects themselves are in fact directly excited via stellar wind-molecular cloud interactions, thus invalidating the hypothesis that H-H objects are pure reflection nebulae. Nevertheless, Grasdalen's pioneering discovery of infrared sources associated with these objects, combined with the infrared survey results, led to a veritable explosion of infrared and molecular line studies of star-forming regions. Grasdalen was also a major contributor to early attempts to understand the nature of intermediate mass young stars - the Herbig Ae/Be stars. His work demonstrated both their pre-main sequence nature via surface gravity measurements and that these objects share infrared properties in common with their lower mass counterparts. Results from these studies were summarized in a review published in "Annual Reviews of Astronomy and Astrophysics" in 1975. This was an early attempt to provide a comprehensive overview of star-formation in molecular cloud complexes and to link the emerging results from mm-wave and infrared observations. Perhaps as noteworthy as the overview was his introduction of the term ``Young Stellar Object" or YSO. In part, this term was invented by Grasdalen as a reaction to the term ``QSO", which in those days (and indeed today) seemed to create an aura of mystery, seductive both to the public and the astronomical community; we star-formation types hoped that YSO would do the same for our field! In 1978, Grasdalen left Kitt Peak for the University of Wyoming where, along with Bob Gehrz and John Hackwell, he made the Mt. Jelm 2.1-meter telescope a world-leading facility for infrared studies. His research interests evolved to include, in addition to YSO research, infrared spectroscopic study of novae, a field that he, Gehrz and Hackwell pioneered and which Bob Gehrz has carried forward, creating an impressive and important oeuvre. Grasdalen was a mentor to a generation of graduates from the University of Wyoming including Kathleen deGioia-Eastwood, Matthew Greenhouse, Karl Klett, Gregory Sloan, Jill Price, Michael Castelaz, Craig Gullixson and Thomas Hayward. To a person, they spoke to the high standards he set, his constant expectation of excellence and critical thinking, the amazing range and depth of his knowledge, and his incredibly creative mind. Following important and influential service on the Optical-Infrared panel for the 1990 decadal survey, Gary left the University of Wyoming and, for awhile (and much to our collective loss), astronomy. Gary was a very private and, in many ways, a wary person. His decision may have been linked to a need for a break from a lifetime of pressure. In the early 1980s, Gary acknowledged that he was gay, a fact which for years he carefully hid from his friends and colleagues. While he found much support at the University of Wyoming (and elsewhere), both subtle and rampant homophobia had to have an affect on someone who was both unusually sensitive and filled with self-doubt. With increasing frequency, whatever Gary may have felt deep within led to bouts of self-destructive behavior. At least it seemed that way to his friends and colleagues; to him, it may have been release. A sad consequence was his contracting AIDS. During the 1990s, Gary ran a non-alcoholic bar in Denver, and according to some, was at relative peace. Apparently, his love for astronomy was still deeply felt and he ultimately returned to work during his last years at the Jet Propulsion Laboratory's Table Mountain Observatory. There, he once again brought his expertise in telescope control systems to bear to upgrade the observatory and enable tracking of rapidly moving objects. He continued to work at Table Mountain until a few weeks before passing away from complications associated with AIDS. We will miss his acid, sometimes black humor, his enjoyment of a stimulating argument, his seemingly off-the-wall, but always, in retrospect incredibly insightful comments. He accomplished much and, perhaps had he found peace and acceptance earlier, could have accomplished so much more. His two sisters, Lavon Engen of Naples, Florida and Janet Stallerin of Albert Lean, Minnesota, survive Gary.

Guidelines, editors, pharma and the biological paradigm shift.

PubMed

Singh, Ajai R; Singh, Shakuntala A

2007-01-01

Private investment in biomedical research has increased over the last few decades. At most places it has been welcomed as the next best thing to technology itself. Much of the intellectual talent from academic institutions is getting absorbed in lucrative positions in industry. Applied research finds willing collaborators in venture capital funded industry, so a symbiotic growth is ensured for both.There are significant costs involved too. As academia interacts with industry, major areas of conflict of interest especially applicable to biomedical research have arisen. They are related to disputes over patents and royalty, hostile encounters between academia and industry, as also between public and private enterprise, legal tangles, research misconduct of various types, antagonistic press and patient-advocate lobbies and a general atmosphere in which commercial interest get precedence over patient welfare.Pharma image stinks because of a number of errors of omission and commission. A recent example is suppression of negative findings about Bayer's Trasylol (Aprotinin) and the marketing maneuvers of Eli Lilly's Xigris (rhAPC). Whenever there is a conflict between patient vulnerability and profit motives, pharma often tends to tilt towards the latter. Moreover there are documents that bring to light how companies frequently cross the line between patient welfare and profit seeking behaviour.A voluntary moratorium over pharma spending to pamper drug prescribers is necessary. A code of conduct adopted recently by OPPI in India to limit pharma company expenses over junkets and trinkets is a welcome step.Clinical practice guidelines (CPG) are considered important as they guide the diagnostic/therapeutic regimen of a large number of medical professionals and hospitals and provide recommendations on drugs, their dosages and criteria for selection. Along with clinical trials, they are another area of growing influence by the pharmaceutical industry. For example, in a relatively recent survey of 2002, it was found that about 60% of 192 authors of clinical practice guidelines reported they had financial connections with the companies whose drugs were under consideration. There is a strong case for making CPGs based not just on effectivity but cost effectivity. The various ramifications of this need to be spelt out. Work of bodies like the Appraisal of Guidelines Research and Evaluation (AGREE) Collaboration and Guidelines Advisory Committee (GAC) are also worth a close look.Even the actions of Foundations that work for disease amelioration have come under scrutiny. The process of setting up 'Best Practices' Guidelines for interactions between the pharmaceutical industry and clinicians has already begun and can have important consequences for patient care. Similarly, Good Publication Practice (GPP) for pharmaceutical companies have also been set up aimed at improving the behaviour of drug companies while reporting drug trialsThe rapidly increasing trend toward influence and control by industry has become a concern for many. It is of such importance that the Association of American Medical Colleges has issued two relatively new documents - one, in 2001, on how to deal with individual conflicts of interest; and the other, in 2002, on how to deal with institutional conflicts of interest in the conduct of clinical research. Academic Medical Centers (AMCs), as also medical education and research institutions at other places, have to adopt means that minimize their conflicts of interest.Both medical associations and research journal editors are getting concerned with individual and institutional conflicts of interest in the conduct of clinical research and documents are now available which address these issues. The 2001 ICMJE revision calls for full disclosure of the sponsor's role in research, as well as assurance that the investigators are independent of the sponsor, are fully accountable for the design and conduct of the trial, have independent access to all trial data and control all editorial and publication decisions. However the findings of a 2002 study suggest that academic institutions routinely participate in clinical research that does not adhere to ICMJE standards of accountability, access to data and control of publication.There is an inevitable slant to produce not necessarily useful but marketable products which ensure the profitability of industry and research grants outflow to academia. Industry supports new, not traditional, therapies, irrespective of what is effective. Whatever traditional therapy is supported is most probably because the company concerned has a product with a big stake there, which has remained a 'gold standard' or which that player thinks has still some 'juice' left.Industry sponsorship is mainly for potential medications, not for trying to determine whether there may be non-pharmacological interventions that may be equally good, if not better. In the paradigm shift towards biological psychiatry, the role of industry sponsorship is not overt but probably more pervasive than many have realised, or the right thinking may consider good, for the health of the branch in the long run.An issue of major concern is protection of the interests of research subjects. Patients agree to become research subjects not only for personal medical benefit but, as an extension, to benefit the rest of the patient population and also advance medical research.We all accept that industry profits have to be made, and investment in research and development by the pharma industry is massive. However, we must also accept there is a fundamental difference between marketing strategies for other entities and those for drugs.The ultimate barometer is patient welfare and no drug that compromises it can stand the test of time. So, how does it make even commercial sense in the long term to market substandard products? The greatest mistake long-term players in industry may make is try to adopt the shady techniques of the upstart new entrant. Secrecy of marketing/sales tactics, of the process of manufacture, of other strategies and plans of business expansion, of strategies to tackle competition are fine business tactics. But it is critical that secrecy as a tactic not extend to reporting of research findings, especially those contrary to one's product.Pharma has no option but to make a quality product, do comprehensive adverse reaction profiles, and market it only if it passes both tests.Why does pharma adopt questionable tactics? The reasons are essentially two:What with all the constraints, a drug comes to the pharmacy after huge investments. There are crippling overheads and infrastructure costs to be recovered. And there are massive profit margins to be maintained. If these were to be dependent only on genuine drug discoveries, that would be taking too great a risk.Industry players have to strike the right balance between profit making and credibility. In profit making, the marketing champions play their role. In credibility ratings, researchers and paid spokes-persons play their role. All is hunky dory till marketing is based on credibility. When there is nothing available to make for credibility, something is projected as one and marketing carried out, in the calculated hope that profits can accrue, since profit making must continue endlessly. That is what makes pharma adopt even questionable means to make profits.Essentially, there are four types of drugs. First, drugs that work and have minimal side-effects; second, drugs which work but have serious side-effects; third, drugs that do not work and have minimal side-effects; and fourth, drugs which work minimally but have serious side-effects. It is the second and fourth types that create major hassles for industry. Often, industry may try to project the fourth type as the second to escape censure.The major cat and mouse game being played by conscientious researchers is in exposing the third and fourth for what they are and not allowing industry to palm them off as the first and second type respectively. The other major game is in preventing the second type from being projected as the first. The third type are essentially harmless, so they attract censure all right and some merriment at the antics to market them. But they escape anything more than a light rap on the knuckles, except when they are projected as the first type.What is necessary for industry captains and long-term players is to realise:Their major propelling force can only be producing the first type. 2. They accept the second type only till they can lay their hands on the first. 3. The third type can be occasionally played around with to shore up profits, but never by projecting them as the first type. 4. The fourth type are the laggards, real threat to credibility and therefore do not deserve any market hype or promotion.In finding out why most pharma indulges in questionable tactics, we are lead to some interesting solutions to prevent such tactics with the least amount of hassles for all concerned, even as both profits and credibility are kept intact.

Guidelines, Editors, Pharma And The Biological Paradigm Shift

PubMed Central

Singh, Ajai R.; Singh, Shakuntala A.

2007-01-01

Private investment in biomedical research has increased over the last few decades. At most places it has been welcomed as the next best thing to technology itself. Much of the intellectual talent from academic institutions is getting absorbed in lucrative positions in industry. Applied research finds willing collaborators in venture capital funded industry, so a symbiotic growth is ensured for both. There are significant costs involved too. As academia interacts with industry, major areas of conflict of interest especially applicable to biomedical research have arisen. They are related to disputes over patents and royalty, hostile encounters between academia and industry, as also between public and private enterprise, legal tangles, research misconduct of various types, antagonistic press and patient-advocate lobbies and a general atmosphere in which commercial interest get precedence over patient welfare. Pharma image stinks because of a number of errors of omission and commission. A recent example is suppression of negative findings about Bayer's Trasylol (Aprotinin) and the marketing maneuvers of Eli Lilly's Xigris (rhAPC). Whenever there is a conflict between patient vulnerability and profit motives, pharma often tends to tilt towards the latter. Moreover there are documents that bring to light how companies frequently cross the line between patient welfare and profit seeking behaviour. A voluntary moratorium over pharma spending to pamper drug prescribers is necessary. A code of conduct adopted recently by OPPI in India to limit pharma company expenses over junkets and trinkets is a welcome step. Clinical practice guidelines (CPG) are considered important as they guide the diagnostic/therapeutic regimen of a large number of medical professionals and hospitals and provide recommendations on drugs, their dosages and criteria for selection. Along with clinical trials, they are another area of growing influence by the pharmaceutical industry. For example, in a relatively recent survey of 2002, it was found that about 60% of 192 authors of clinical practice guidelines reported they had financial connections with the companies whose drugs were under consideration. There is a strong case for making CPGs based not just on effectivity but cost effectivity. The various ramifications of this need to be spelt out. Work of bodies like the Appraisal of Guidelines Research and Evaluation (AGREE) Collaboration and Guidelines Advisory Committee (GAC) are also worth a close look. Even the actions of Foundations that work for disease amelioration have come under scrutiny. The process of setting up ‘Best Practices’ Guidelines for interactions between the pharmaceutical industry and clinicians has already begun and can have important consequences for patient care. Similarly, Good Publication Practice (GPP) for pharmaceutical companies have also been set up aimed at improving the behaviour of drug companies while reporting drug trials The rapidly increasing trend toward influence and control by industry has become a concern for many. It is of such importance that the Association of American Medical Colleges has issued two relatively new documents - one, in 2001, on how to deal with individual conflicts of interest; and the other, in 2002, on how to deal with institutional conflicts of interest in the conduct of clinical research. Academic Medical Centers (AMCs), as also medical education and research institutions at other places, have to adopt means that minimize their conflicts of interest. Both medical associations and research journal editors are getting concerned with individual and institutional conflicts of interest in the conduct of clinical research and documents are now available which address these issues. The 2001 ICMJE revision calls for full disclosure of the sponsor's role in research, as well as assurance that the investigators are independent of the sponsor, are fully accountable for the design and conduct of the trial, have independent access to all trial data and control all editorial and publication decisions. However the findings of a 2002 study suggest that academic institutions routinely participate in clinical research that does not adhere to ICMJE standards of accountability, access to data and control of publication. There is an inevitable slant to produce not necessarily useful but marketable products which ensure the profitability of industry and research grants outflow to academia. Industry supports new, not traditional, therapies, irrespective of what is effective. Whatever traditional therapy is supported is most probably because the company concerned has a product with a big stake there, which has remained a ‘gold standard’ or which that player thinks has still some ‘juice’ left. Industry sponsorship is mainly for potential medications, not for trying to determine whether there may be non-pharmacological interventions that may be equally good, if not better. In the paradigm shift towards biological psychiatry, the role of industry sponsorship is not overt but probably more pervasive than many have realised, or the right thinking may consider good, for the health of the branch in the long run. An issue of major concern is protection of the interests of research subjects. Patients agree to become research subjects not only for personal medical benefit but, as an extension, to benefit the rest of the patient population and also advance medical research. We all accept that industry profits have to be made, and investment in research and development by the pharma industry is massive. However, we must also accept there is a fundamental difference between marketing strategies for other entities and those for drugs. The ultimate barometer is patient welfare and no drug that compromises it can stand the test of time. So, how does it make even commercial sense in the long term to market substandard products? The greatest mistake long-term players in industry may make is try to adopt the shady techniques of the upstart new entrant. Secrecy of marketing/sales tactics, of the process of manufacture, of other strategies and plans of business expansion, of strategies to tackle competition are fine business tactics. But it is critical that secrecy as a tactic not extend to reporting of research findings, especially those contrary to one's product. Pharma has no option but to make a quality product, do comprehensive adverse reaction profiles, and market it only if it passes both tests. Why does pharma adopt questionable tactics? The reasons are essentially two: What with all the constraints, a drug comes to the pharmacy after huge investments. There are crippling overheads and infrastructure costs to be recovered. And there are massive profit margins to be maintained. If these were to be dependent only on genuine drug discoveries, that would be taking too great a risk. Industry players have to strike the right balance between profit making and credibility. In profit making, the marketing champions play their role. In credibility ratings, researchers and paid spokes-persons play their role. All is hunky dory till marketing is based on credibility. When there is nothing available to make for credibility, something is projected as one and marketing carried out, in the calculated hope that profits can accrue, since profit making must continue endlessly. That is what makes pharma adopt even questionable means to make profits. Essentially, there are four types of drugs. First, drugs that work and have minimal side-effects; second, drugs which work but have serious side-effects; third, drugs that do not work and have minimal side-effects; and fourth, drugs which work minimally but have serious side-effects. It is the second and fourth types that create major hassles for industry. Often, industry may try to project the fourth type as the second to escape censure. The major cat and mouse game being played by conscientious researchers is in exposing the third and fourth for what they are and not allowing industry to palm them off as the first and second type respectively. The other major game is in preventing the second type from being projected as the first. The third type are essentially harmless, so they attract censure all right and some merriment at the antics to market them. But they escape anything more than a light rap on the knuckles, except when they are projected as the first type. What is necessary for industry captains and long-term players is to realise: Their major propelling force can only be producing the first type. 2. They accept the second type only till they can lay their hands on the first. 3. The third type can be occasionally played around with to shore up profits, but never by projecting them as the first type. 4. The fourth type are the laggards, real threat to credibility and therefore do not deserve any market hype or promotion. In finding out why most pharma indulges in questionable tactics, we are lead to some interesting solutions to prevent such tactics with the least amount of hassles for all concerned, even as both profits and credibility are kept intact. PMID:22058616

News & Announcements

NASA Astrophysics Data System (ADS)

1999-09-01

Unification of Journal Options Beginning in 2000, the Journal subscription form will get much simpler and your Journal subscription will bring you even more than previously. Below is an outline of how the new system will work for individuals. Subscriptions for Individuals

• Beginning September 1, 1999, all Journal print subscriptionscurrent, continuing, new, and renewalwill bring you monthly print issues and give you full access to JCE Online+everything that we have online.
• If you don't want paper copy of your issue, there is a No-Print Optionwe donate your print copy to our Teacher Workshop Program and you have full access to everything online.
• If you do want both paper and online but don't want to keep back issuessaving storage spaceyou can purchase JCE CD each year.

• JCE Online FAQs (March 1999, p 446)
• JCE Online 99 (April 1999, p 584)
• JCE Feature Columns (May 1999, p 718)
• Molecular Modeling (June 1999, p 871)

Proposal Deadlines

National Science Foundation Division of Undergraduate Education (DUE)

• Course, Curriculum, and Laboratory Improvement (CCLI) June 5, 2000 (anticipated)
• NSF Computer Science, Engineering, and Mathematics Scholarships Program (CSEMS) TBA
• Advanced Techological Education (ATE) Preliminary April 13, 2000 (anticipated) Formal Oct. 14, 1999, and Oct. 13, 2000 (anticipated)
• NSF Graduate Fellows in K-12 Education (GK-12) TBA (anticipated late spring 2000)
• Online DUE forms available at http://www.ehr.nsf.gov/EHR/DUE/documents/general/forms/forms.htm
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The Camille and Henry Dreyfus Foundation, Inc.

• Camille Dreyfus Teacher-Scholar Awards Program: November 15, 1999, and November 15, 2000
• Henry Dreyfus Teacher-Scholar Awards Program: June 30, 2000
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• Faculty Start-up Grants for Undergraduate Institutions: May 15, 2000
• Scholar/Fellow Program for Undergraduate Institutions: June 30, 2000
• Special Grant Program in the Chemical Sciences: Preliminary Proposals: June 15, 2000 Complete Proposals: September 1, 2000
• Postdoctoral Program in Environmental Chemistry: March 1, 2000
• Senior Scientist Mentor: September 1, 1999, and September 1, 2000

Research Corporation

• Cottrell College Science Awards: May 15 and November 15
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