The Effect of Prescription Drug Copayments on Utilization and Associated Overall Costs

The purpose of this research is to study the effect of an increase on prescription drug copayments on utilization and associated costs. Using a cross-sectional, time series, cohort study design consisting of 2,389 members continuously enrolled for 24 months, from one large employer enrolled in a Midwest HMO, this study compares 1998 prescription drug costs and utilization when there was a $0 copay, to 1999 costs utilization after a$5 copay was implemented. Using the difference-of-means test, empirical results indicate that: 1) Drug utilization (measured by prescription claims PMPY) declined from 1998 to 1999 but the decline was not statistically significant. 2) Total drug costs PMPY hcreased significantly (at the 1% level) from 1998 to 1999 because of an increased use of brand over generic drugs, which led to a statistically significant increase in ingredient cost. 3) However, overall drug costs to the HMO showed a statistically significant decrease of 1.6% from 1998 to 1999 for three reasons: a) The $5 copayment was introduced in 1999. b) There was a statistically significant decrease in fill fee PMPY to the HMO from 1998 to 1999. c) There was a statistically significant increase in the add-in-fee PMPY from 1998 to 1999. These three factors all contributed to the statistically significant reduction in prescription drug costs to the HMO from 1998 to 1999. Therefore, this study shows that an increase in a prescription drug copayment can provide substantial savings to both employers and HMOs without becoming a deterrent to overall utilization.Master'sCollege of Arts and Sciences: Public AdministrationUniversity of Michiganhttp://deepblue.lib.umich.edu/bitstream/2027.42/117772/1/Zell.pd

Exploring the functional domain and the target of the tetanus toxin light chain in neurohypophysial terminals

The tetanus toxin light chain blocks calcium induced vasopressin release from neurohypophysial nerve terminals. Here we show that histidine residue 233 within the putative zinc binding motif of the tetanus toxin light chain is essential for the inhibition of exocytosis, in the rat. The zinc chelating agent dipicolinic acid as well as captopril, an inhibitor of zinc-dependent peptidases, counteract the effect of the neurotoxin. Synthetic peptides, the sequences of which correspond to motifs present in the cytoplasmic domain of the synaptic vesicle membrane protein synaptobrevin 1 and 2, prevent the effect of the tetanus toxin light chain. Our results indicate that zinc bound to the zinc binding motif constitutes the active site of the tetanus toxin light chain. Moreover they suggest that cleavage of synaptobrevin by the neurotoxin causes the inhibition of exocytotic release of vasopressin from secretory granules

ProDGe: investigating protein-protein interactions at the domain level

An important goal of systems biology is the identification and investigation of known and predicted protein-protein interactions to obtain more information about new cellular pathways and processes. Proteins interact via domains, thus it is important to know which domains a protein contains and which domains interact with each other. Here we present the Java^TM^ program ProDGe (Protein Domain Gene), which visualizes existing and suggests novel domain-domain interactions and protein-protein interactions at the domain level. The comprehensive dataset behind ProDGe consists of protein, domain and interaction information for both layers, collected and combined appropriately from UniProt, Pfam, DOMINE and IntAct. Based on known domain interactions, ProDGe suggests novel protein interactions and assigns them to four confidence classes, depending on the reliability of the underlying domain interaction. Furthermore, ProDGe is able to identify potential homologous interaction partners in other species, which is particularly helpful when investigating poorly annotated species. We further evaluated and compared experimentally identified protein interactions from IntAct with domain interactions from DOMINE for six species and noticed that 31.13% of all IntAct protein interactions in all six species can be mapped to the actual interacting domains. ProDGe and a comprehensive documentation are freely available at http://www.cogsys.cs.uni-tuebingen.de/software/ProDGe

Malat Metabolismus und die Rolle der NADP-Malat Enzym Isoformen in der C3-Modellpflanze A. thaliana

Obwohl Malat und Fumarat in eine Vielzahl von Stoffwechselweg der Pflanze involviert sind, bleibt ihre Funktion als Kohlenstoffquelle in C3-Pflanzen weitgehend ungeklärt. In dieser Arbeit wurden Arabidopsis thaliana Pflanzen und Stärkefreimutanten adg1 (ADG-Glukose-Phyrophosphorylase1 null Mutante) und pgm1 und sft1 (Phosphoglucomutase1 null Mutante), die ein plastidäres Mais-NADP-ME (MEm) überexprimierten, wurden genutzt um die Auswirkung eines extrem niedrigen Malat- und Fumarat-Gehalt au die Physiologie von C3-Pflanzen zu untersuchen. Die MEm-Überexpressions-Pflanzen entwickelten einen Kohlenstoffmangel-Phänotypen besonders unter Kurz-Tag-Bedingungen. Die Beobachteten Ergebnisse dieses Phänotyp untermauern die physiologische Rolle von Malat und Fumarat als essenzielle transiente Kohlenstoffquellen in C3-Pflanzen wie A. thaliana. Wir postulieren, dass das niedrige Level von organischen Säuren, das einem Karbohydrat-Mangel am Ende der Nacht folgt, als initiales Signal dient und eine Kaskade von Abläufen verursacht, die letztlich zur veränderten Substratnutzung in der Respiration hin zu hoch reduzierten Substraten, wie Fettsäuren und Proteinen während der langen Nachtphase bewirken. Dem folgend unterstützen unsere Ergebnisse die Annahme, das die organischen Säuren, Malat und Fumarat, äußerst wichtige C-Quellen im Metabolismus von A. thaliana darstellen. NADP-Malat-Enzym (NADP-ME, E.C. 1.1.1.40) katalysiert die oxidative Dekarboxylierung von L-Malat unter Gewinnung von Pyruvat, CO2 und NADPH. Obwohl die Rolle von NADP-ME in der C4-Photosynthese bekannt ist, bleiben die physiologischen Funktionen der C3-Isoformen bisher ungeklärt. Die Analyse des transkriptionalen Coexpressionsmuster zeigt, dass NADP-ME2 in Verbindung mit Genen steht, die in die Pathogenabwehr involviert sind. Unsere Arbeit zeigt, dass die gesamte NADP-ME Aktivität nach Infiltration mit pilzlichen und bakteriellen Elizitoren und nach Infektion mit dem hemibiotrophen pilzlichen Pathogen Colletotrichum higginsianum induziert wurde. Des weiteren konnte mit Funktionsverlust-Mutanten und mehreren biochemischen und physiologischen Methoden gezeigt werden, dass die beobachtete Aktivitätsänderung durch NADP-ME2 verursacht wurde und der Verlust des zytosolischen NADP-ME2 eine erhöhte Empfindlichkeit gegenüber Infektionen zur Folge hat. Unsere Ergebnisse lassen vermuten, dass NADP-ME2 in Mechanismen involviert ist, die NADPH für die ROS-Produktion bereitstellen könnten. NADP-ME3 könnte eine mögliche Rolle im Abbau der primären oder sekundären PCM-Wand während Pollen Entwicklung

Evolution of E2 transition strength in deformed hafnium isotopes from new measurements on 172^{172}Hf, 174^{174}Hf, and 176^{176}Hf

The available data for E2 transition strengths in the region between neutron-deficient Hf and Pt isotopes are far from complete. More and precise data are needed to enhance the picture of structure evolution in this region and to test state-of-the-art nuclear models. In a simple model, the maximum collectivity is expected at the middle of the major shell. However, for actual nuclei, this picture may no longer be the case, and one should use a more realistic nuclear-structure model. We address this point by studying the spectroscopy of Hf. We remeasure the 2^+_1 half-lives of 172,174,176Hf, for which there is some disagreement in the literature. The main goal is to measure, for the first time, the half-lives of higher-lying states of the rotational band. The new results are compared to a theoretical calculation for absolute transition strengths. The half-lives were measured using \gamma-\gamma and conversion-electron-\gamma delayed coincidences with the fast timing method. For the determination of half-lives in the picosecond region, the generalized centroid difference method was applied. For the theoretical calculation of the spectroscopic properties, the interacting boson model is employed, whose Hamiltonian is determined based on microscopic energy-density functional calculations. The measured 2^+_1 half-lives disagree with results from earlier \gamma-\gamma fast timing measurements, but are in agreement with data from Coulomb excitation experiments and other methods. Half-lives of the 4^+_1 and 6^+_1 states were measured, as well as a lower limit for the 8^+_1 states. We show the importance of the mass-dependence of effective boson charge in the description of E2 transition rates in chains of nuclei. It encourages further studies of the microscopic origin of this mass dependence. New data on transition rates in nuclei from neighboring isotopic chains could support these studies.Comment: 16 pages, 16 figures, 7 tables; Abstract shortened due to character limi

Estrogens Determine Adherens Junction Organization and E-Cadherin Clustering in Breast Cancer Cells via Amphiregulin

Estrogens play an important role in the development and progression of human cancers, particularly in breast cancer. Breast cancer progression depends on the malignant destabilization of adherens junctions (AJs) and disruption of tissue integrity. We found that estrogen receptor alpha (ER alpha) inhibition led to a striking spatial reorganization of AJs and microclustering of E-Cadherin (E-Cad) in the cell membrane of breast cancer cells. This resulted in increased stability of AJs and cell stiffness and a reduction of cell motility. These effects were actomyosindependent and reversible by estrogens. Detailed investigations showed that the ERa target gene and epidermal growth factor receptor (EGFR) ligand Amphiregulin (AREG) essentially regulates AJ reorganization and E-Cad microclustering. Our results not only describe a biological mechanism for the organization of AJs and the modulation of mechanical properties of cells but also provide a new perspective on how estrogens and anti-estrogens might influence the formation of breast tumors

Modeling metabolic networks in C. glutamicum: a comparison of rate laws in combination with various parameter optimization strategies

<p>Abstract</p> <p>Background</p> <p>To understand the dynamic behavior of cellular systems, mathematical modeling is often necessary and comprises three steps: (1) experimental measurement of participating molecules, (2) assignment of rate laws to each reaction, and (3) parameter calibration with respect to the measurements. In each of these steps the modeler is confronted with a plethora of alternative approaches, e. g., the selection of approximative rate laws in step two as specific equations are often unknown, or the choice of an estimation procedure with its specific settings in step three. This overall process with its numerous choices and the mutual influence between them makes it hard to single out the best modeling approach for a given problem.</p> <p>Results</p> <p>We investigate the modeling process using multiple kinetic equations together with various parameter optimization methods for a well-characterized example network, the biosynthesis of valine and leucine in <it>C. glutamicum</it>. For this purpose, we derive seven dynamic models based on generalized mass action, Michaelis-Menten and convenience kinetics as well as the stochastic Langevin equation. In addition, we introduce two modeling approaches for feedback inhibition to the mass action kinetics. The parameters of each model are estimated using eight optimization strategies. To determine the most promising modeling approaches together with the best optimization algorithms, we carry out a two-step benchmark: (1) coarse-grained comparison of the algorithms on all models and (2) fine-grained tuning of the best optimization algorithms and models. To analyze the space of the best parameters found for each model, we apply clustering, variance, and correlation analysis.</p> <p>Conclusion</p> <p>A mixed model based on the convenience rate law and the Michaelis-Menten equation, in which all reactions are assumed to be reversible, is the most suitable deterministic modeling approach followed by a reversible generalized mass action kinetics model. A Langevin model is advisable to take stochastic effects into account. To estimate the model parameters, three algorithms are particularly useful: For first attempts the settings-free Tribes algorithm yields valuable results. Particle swarm optimization and differential evolution provide significantly better results with appropriate settings.</p

Demographic, exposure and clinical characteristics in a multinational registry of engineered stone workers with silicosis

Polvo; Salud ocupacional; Pruebas de función respiratoriaDust; Occupational health; Respiratory function testsPols; Salut ocupacional; Proves de funció respiratòriaObjectives To investigate differences in workplace exposure, demographic and clinical findings in engineered stone (ES) workers from a multinational consortium using the Engineered Stone Silicosis Investigators (ESSI) Global Silicosis Registry. Methods With ethics board approval in Israel, Spain, Australia and the USA, ES workers ages 18+ with a physician diagnosis of work-related silicosis were enrolled. Demographic, occupational, radiologic, pulmonary function and silica-related comorbidity data were compared cross-sectionally among countries using analysis of variance, Fisher’s exact tests and logistic regression. Results Among 169 ES workers with silicosis, most were men, with mean age 51.7 (±11.4) years. Mean work tenure in stone fabrication or masonry was 19.9 (±9.8) years. Different methods of case ascertainment explained some inter-country differences, for example, workers in Queensland, Australia with a state-based surveillance program were likely to be identified earlier and with shorter work tenure. Overall, 32.5% of workers had progressive massive fibrosis, the most severe form of dust-related pneumoconiosis, of whom 18.5% reported ≤10 years of work tenure. Lung function impairment including restriction, reduced diffusion capacity and hypoxaemia was common, as was autoimmunity. Conclusions Findings from a multinational registry represent a unique effort to compare demographic, exposure and clinical information from ES workers with silicosis, and suggest a substantial emerging population of workers worldwide with severe and irreversible silica-associated diseases. This younger worker population is at high risk for disease progression, multiple comorbidities and severe disability. The ESSI registry provides an ongoing framework for investigating epidemiological trends and developing prospective studies for prevention and treatment of these workers.Work conducted at National Jewish Health was partially supported by the Reuben M Cherniack fellowship award. Work conducted in Israel was partially supported by the Committee for Research and Prevention in Occupational Safety and Health (56/13)

Ghosts of the past and dreams of the future: the impact of temporal focus on responses to contextual ingroup devaluation.

addresses: University of Exeter, Exeter, UK. [email protected]: Journal Article; Research Support, Non-U.S. Gov'tCopyright © 2012 SAGE Publications. Author's draft version; post-print. Final version published by Sage available on Sage Journals Online http://online.sagepub.com/The authors investigated the impact of temporal focus on group members' responses to contextual ingroup devaluation. Four experimental studies demonstrated that following an induction of negative ingroup evaluation, participants primed with a past temporal focus reported behavioral intentions more consistent with this negative appraisal than participants primed with a future temporal focus. This effect was apparent only when a negative (but not a positive) evaluation was induced, and only among highly identified group members. Importantly, the interplay between temporal focus and group identification on relevant intentions was mediated by individual self-esteem, suggesting that focus on the future may be conducive to separating negative ingroup appraisals from individual self-evaluations. Taken together, the findings suggest that high identifiers' responses to ingroup evaluations may be predicated on their temporal focus: A focus on the past may lock such individuals within their group's history, whereas a vision of the future may open up opportunities for change