Improving anemia management with less frequently dosed erythropoiesis stimulating agents

Introduction and Aims: The process of delivering erythropoiesis stimulating agents (ESAs) to hemodialysis patients (HD) is complex. Many European countries are requiring centers to document this process. To date, there has not been any comprehensive description of the operational aspects of ESA delivery in Europe. The objective of the Mercurius study was to describe the entire process of ESA delivery in dialysis centers. In addition, we explored the benefits of less frequent dosing. Methods: A conceptual model was developed to classify the sub-processes in the pharmacy, dialysis unit, waste unit, and back office. Within each dialysis unit activities associated with dose determination, ordering procedures, receipt and storage of ESAs, and ESA administration were measured. Within the pharmacy, ordering from supplier, receiving and storing, and delivering ESA to the dialysis unit were measured. The amount of time and materials associated with waste disposal and back office activities were also observed. We also evaluated the impact of less frequent dosing on the resources required to perform anemia management for HD patients. Structured interviews with staff were used to develop a comprehensive list of processes, sub-processes, and activities that are routinely followed to order, register, administer, and dispose of waste associated with ESAs. Each activity was evaluated to determine if less frequent dosing influenced the amount of resources required. A model was developed to estimate the change in resources consumed using less frequent dosing regimens. Results: Eight centers from 5 European countries (Belgium, France, Italy, Sweden, and Switzerland) participated in the study. The number of HD patients in each center ranged from 42 to 707 (mean=175). Across all of the centers, patients received a variety of dosing regimens (eg, TIW, BIW, QW and Q2W). The mean (±SD) time spent for the pharmacy to order an ESA from the supplier was 6.1 (±8.7) minutes; time spent in the dialysis unit and pharmacy for receiving and storing ESPs was 5.3 (±5.3) and 10.0 (±10.9) minutes, respectively; and time spent administering each injection was 6.4 (±6.5) minutes. Switching from current dosing practices to Q2W could decrease the mean number of syringes used from 12,420 to 5,085 per year. We estimate a reduction in the number of disinfective tissues and liquids of 58% and 71%, respectively by switching from current practice to dosing ESAs Q2W. Conclusions: There was significant variation in the time that it takes to perform routine ESA activities. We estimate that a reduction in resources required to manage anemia can be obtained by reducing the frequency of administration from the current mix of ESAs. These resources could be redeployed for patient care.

Generation of mouse-induced pluripotent stem cells by transient expression of a single nonviral polycistronic vector

Induced pluripotent stem (iPS) cells have generated keen interestdue to their potential use in regenerative medicine. They havebeen obtained from various cell types of both mice and humans byexogenous delivery of different combinations of Oct4, Sox2, Klf4,c-Myc, Nanog, and Lin28. The delivery of these transcription factorshas mostly entailed the use of integrating viral vectors (retrovirusesor lentiviruses), carrying the risk of both insertional mutagenesisand oncogenesis due to misexpression of these exogenousfactors. Therefore, obtaining iPS cells that do not carry integratedtransgene sequences is an important prerequisite for their eventualtherapeutic use. Here we report the generation of iPS cell linesfrom mouse embryonic fibroblasts with no evidence of integrationof the reprogramming vector in their genome, achieved by nucleofectionof a polycistronic construct coexpressing Oct4, Sox2, Klf4,and c-Myc

Space Utilization and Building Study for the Department of General Services, October 9, 2000

Purposes of this Report: • Recommend the most logical and economical options to address state governmental space needs in the Polk County metropolitan area to the year 2010. • Include building size, location, phasing, financing, method of project delivery and estimated cost. • Develop a software tool to compare costs of leasing vs. ownership of space. Methodology: Identify: 1. Current amount and location of owned and leased space, by agency; 2. Types of space and whether best located on or off of the Capitol Complex; 3. Utilization of space, noting over-crowding and under-utilization; 4. Current number of workstations for full and part time employees, Personnel Employment Organization (PEO) workers, contractors, interns, etc.; and, 5. History of staff levels to assist in the prediction of staff growth. Scope: This report focuses on 10 state-owned buildings located on the Capitol Complex and 48 leased spaces in the Polk County metropolitan area. (See Figures 1 and 2.) • Due to a separate space study under way by the Legislature, implications of area and staff for the State Capitol building are included only for the Governor, Lieutenant Governor, Treasurer, Secretary of State, Auditor and the Department of Management. • Because it is largely a museum building that does not have office space available for other agencies, the area and staff of the Historical Building are not fully addressed. • Only the parking implications of the new Judicial Building are included in this study because the building space is under the jurisdiction of the Judicial Branch and not available for other agencies. Several state-owned buildings are not included in the scope of this report, generally because they have highly focused purposes, and their space is not available for assignment to other agencies. Several leased locations are not included for similar reasons, including leases that do not fall within the authority of the Department of General Services.

State of Iowa Space Utilization and Building Study, October 9, 2000

Executive Summary Purposes of this Report: • Recommend the most logical and economical options to address state governmental space needs in the Polk County metropolitan area to the year 2010. • Include building size, location, phasing, financing, method of project delivery and estimated cost. • Develop a software tool to compare costs of leasing vs. ownership of space. Methodology: Identify: 1. Current amount and location of owned and leased space, by agency; 2. Types of space and whether best located on or off of the Capitol Complex; 3. Utilization of space, noting over-crowding and under-utilization; 4. Current number of workstations for full and part time employees, Personnel Employment Organization (PEO) workers, contractors, interns, etc.; and, 5. History of staff levels to assist in the prediction of staff growth. Scope: This report focuses on 10 state-owned buildings located on the Capitol Complex and 48 leased spaces in the Polk County metropolitan area. (See Figures 1 and 2.) • Due to a separate space study under way by the Legislature, implications of area and staff for the State Capitol building are included only for the Governor, Lieutenant Governor, Treasurer, Secretary of State, Auditor and the Department of Management. • Because it is largely a museum building that does not have office space available for other agencies, the area and staff of the Historical Building are not fully addressed. • Only the parking implications of the new Judicial Building are included in this study because the building space is under the jurisdiction of the Judicial Branch and not available for other agencies. Several state-owned buildings are not included in the scope of this report, generally because they have highly focused purposes, and their space is not available for assignment to other agencies. Several leased locations are not included for similar reasons, including leases that do not fall within the authority of the Department of General Services.

Standards for Single Span Prefabricated Bridges, Phase I - Concept Development, TR-663, 2014

In coordination with a Technical Advisory Committee (TAC) consisting of County Engineers and Iowa DOT representatives, the Iowa DOT has proposed to develop a set of standards for a single span prefabricated bridge system for use on the local road system. The purpose of the bridge system is to improve bridge construction, accelerate project delivery, improve worker safety, be cost effective, reduce impacts to the travelling public by reducing traffic disruptions and the duration of detours, and allow local forces to construct the bridges. HDR Inc. was selected by the Iowa DOT to perform the initial concept screening of the bridge system. This Final Report summarizes the initial conceptual effort to investigate potential systems, make recommendations for a preferred system and propose initial details to be tested in the laboratory in Phase 2 of the project. The prefabricated bridge components were to be based on the following preliminary criteria set forth by the TAC. The criteria were to be verified and/ or modified as part of the conceptual development. - 24’ and 30’ roadway widths - Skews of 0o, 15o, and 30o - Span lengths of 30’ – 70’ in 10’ increments using precast concrete beams - Voided box beams could be considered - Limit precast element weight to 45,000 pounds for movement and placement of beams - Beams could be joined transversely with threaded rods - Abutment concepts may included precast as well as an option for cast-in-place abutments with pile foundations In addition to the above criteria, there was an interest to use a single-width prefabricated bridge component to simplify fabrication as well as a desire to utilize non-prestressed concrete systems where possible to allow for precasting of the beam modules by local forces or local precast plants. The SL-1 modular steel bridge rail was identified for use with this single span prefabricated bridge system.

Paineellisten reaktoreiden projektitoimituksen optimointi

Diplomityössä tavoitteena on saada selvitys, jonka avulla yritys löytää toimitusprojekteistaan parannusta ja huomiota vaativat osa-alueet projektimuotoisten toimitusten kustannusrakennetta ja optimointia tarkastelemalla. Näin yritys voi tulevaisuudessa kehittää projektitoimituksen osa-alueita niin että se voi vastata asiakkaiden asettamiin vaatimuksiin sekä haasteisiin entistä nopeammin ja tarkemmin. Tutkimuksen lähtökohtana ovat projektiajattelu sekä siihen liittyvän toimitusketjun prosessit, joiden avulla lähestytään tutkimuksen ongelmaa ja selvitetään koko toimitusprojektin kehitystä vaativat alueet. Tutkimuksessa vaaditut tiedot saavutettiin vapaamuotoisten haastattelujen, yrityksen dokumentteja tutkimalla sekä yhteistyökumppanien avulla. Projektitoimituksen kokonaisvaltainen kehitys vaatii yhteistyötä ja huomiota toimitusketjun jokaisessa osa-alueessa aina raaka-ainelähteiltä loppukäyttäjälle asti. Näin voidaan saavuttaa tietojen avoimuus ja täsmällisyys, jotta päästään parhaaseen lopputulokseen projektitoimituksen osalta. Erityisesti kustannusrakenteen jakauma tuleehuomioida tulevaisuudessa tarkasti tehtäessä projektitoimitukseen liittyviä ratkaisuja. Esivalmistusasteen tarkastelu asetettiin työn alussa yhdeksi tärkeimmäksi tutkimuskohteeksi. Tarkastelussa havaittiin, että valmistusasteen valinnalla voidaan vaikuttaa lähes puoleen reaktorin kustannusrakenteen mukaisista kustannuksista kuten työ-, kuljetus- ja asennuskustannukseen. Myös materiaalikustannukset ovat suuressa roolissa reaktorinkustannusrakenteessa, joten tähän tulee kiinnittää myös huomiota. Muita tutkittavia tekijöitä, jotka pääasiassa vaikuttivat materiaali- ja asennuskustannuksiin työssä olivat paineastiastandardin ja paineluokan sekä valmistuspaikan valinta. Lisäksi huomioitiin toteutuneiden toimitusten eroavaisuuksia teoreettisiin ratkaisuihin ja etsittiin näistä mahdollisia kehitys- ja kustannussäästökohteita.

Projektin onnistumisen kokonaisvaltainen määrittäminen tietojärjestelmätoimitusprojekteissa

Tämän työn tavoitteena on kehittää Basware Finlandille ohjelmistoprojektien onnistumisen arviointiin menetelmä, jolla yritys saa tietoonsa ovatko sen toimittamat järjestelmät todella saavuttaneet asiakkaan projektille asettamat tavoitteet. Työn lähtökohtana on kattava projektin onnistumista koskevan kirjallisuuden tutkiminen ja tämän pohjalta luotava malli projektien onnistumisen mittaamiseen vaikuttavista tekijöistä. Kyseisessä mallissa osoitetaan mitkä tekijät vaikuttavat oleellisesti projektin onnistumisen seurannan suorittamiseen sekä miten projekteja suorittavan organisaation tulisi lähteä kehittämään projektien onnistumisen arviointijärjestelmää. Työn varsinaisena tuloksena syntyi menetelmä, jonka avulla Basware voi seurata toimittamiensa tietojärjestelmäprojektien onnistumista asiakasnäkökulmasta. Lisäksi työssä analysoitiin ja esitettiin tämän perusteella parannusehdotuksia Baswaren tällä hetkellä käyttämää projektipalautekyselyyn.

Projektijohtamisen kehittäminen puutuoteteollisuudessa

Tämän tutkimuksen tavoitteena on selvittää kuinka parannetaan ja kehitetään tuoteosakauppaan perustuvan toimitusprojektin projektinjohtamista ja sitä kautta projektin tehokkuutta projektinhallinnan keinoin. Toimitusprojektissa projektijohtamisesta vastaa käytännössä projektipäällikkö. Tutkimuksen tavoitteena on rakentaa tuoteosakauppaan perustuvaan toimitusprojektiin soveltuva projekti-päällikkövetoinen projektijohtamismalli. Tutkimusmetodina käytettiin case studya eli tapaustutkimusta. Teoriaosassa haettiin kirjallisuudesta tietoa projektista, toimitusprojektista, tuoteosakaupasta, projektijohtamisesta, projektipäällikön tehtävistä, rooleista ja ominaisuuksista, projektijohtamisesta ja suorituskyvystä sekä projektinhallinnan eri osa-alueista. Empiirisessä osassa suoritettiin haastattelututkimus kohdeyrityksessä. Haastattelun tarkoituksena oli tutkia kohdeyrityksen projektijohtamisen nykytilaa. Tämä tutkimus osoittaa, että tuoteosakauppaan perustuvan toimitusprojektin projektijohtamista pystytään parantamaan ja tehostamaan projektinhallinnan keinoin. Lisäksi löydettiin tekijät, jotka ovat hyvän projektijohtamisen takana. Tässä tutkimuksessa rakennettu projektijohtamismalli osoittaa, että projektinhallinnan osa-alueita hyödyntämällä pystytään rakentamaan toimiva projektijohtamismalli.

Developing construction site operations for EPC power plant projects

The purpose of this thesis is to find development areas for site operations in power plant construction projects delivered by Wärtsilä. The inspected operations are subcontractor management, site material management and work scheduling. The contractor's role in EPC project is to respond for engineering, procurement, and construction supervision. Geographical and cultural differences brings challenges for finding development areas as Wärtsilä delivers projects world-wide. Searching for development area is mainly made with survey, which answers were collected from the target company's site personnel. Based on the results, with good planning and preparation various problems would be avoided. An external view for the thesis was collected by an expert interview, which was held to three expe-rienced construction operating executives. Interviewees believed that with the se-lection of right site personnel and clearly defined areas of responsibility will great-ly affect the outcome of the project. Some of the theory has been collected from areas, which have helped to under-stand the inspected operations on site. Improving competence knowledge has been important due to the broad scope of work and the author’s inexperience of the topic. Also generally effective practices from construction projects has been col-lected to the theory part. Functionality of general practices have been reflected together with the results of empirically collected data for Wärtsilä's projects. As a result, a model was generated where development proposals and the benefits from new procedures were presented.

Testing Delivery Systems in Transnational virtual learning: the vocational management training for the european tourism industry (VocMat) case study

This article discusses the lessons learned from developing and delivering the Vocational Management Training for the European Tourism Industry (VocMat) online training programme, which was aimed at providing flexible, online distance learning for the European tourism industry. The programme was designed to address managers ‘need for flexible, senior management level training which they could access at a time and place which fitted in with their working and non-work commitments. The authors present two main approaches to using the Virtual Learning Environment, the feedback from the participants, and the implications of online Technology in extending tourism training opportunities

PEGylated amyloid peptide nanocontainer delivery and release system

A micellar nanocontainer delivery and release system is designed on the basis of a peptide-polymer conjugate. The hybrid molecules self-assemble into micelles comprising a modified amyloid peptide core surrounded by a PEG corona. The modified amyloid peptide previously studied in our group forms helical ribbons based on a beta-sheet motif and contains beta-amino acids that are excluded from the beta-sheet structure, thus being potentially useful as fibrillization inhibitors. In the model peptide-PEG hybrid system studied, enzymatic degradation using alpha-chymotrypsin leads to selective cleavage close to the PEG-peptide linkage, break up of the micelles, and release of peptides in unassociated form. The release of monomeric peptide is useful because aggregation of the released peptide into beta-sheet amyloid fibrils is not observed. This concept has considerable potential in the targeted delivery of peptides for therapeutic applications.

Strategic organization in projects and firms through software integration

As integrated software solutions reshape project delivery, they alter the bases for collaboration and competition across firms in complex industries. This paper synthesises and extends literatures on strategy in project-based industries and digitally-integrated work to understand how project-based firms interact with digital infrastructures for project delivery. Four identified strategies are to: 1) develop and use capabilities to shape the integrated software solutions that are used in projects; 2) co-specialize, developing complementary assets to work repeatedly with a particular integrator firm; 3) retain flexibility by developing and maintaining capabilities in multiple digital technologies and processes; and 4) manage interfaces, translating work into project formats for coordination while hiding proprietary data and capabilities in internal systems. The paper articulates the strategic importance of digital infrastructures for delivery as well as product architectures. It concludes by discussing managerial implications of the identified strategies and areas for further research.

Processanalys vid Color Print Sweden AB med fokusering på prepressavdelningen

This thesis work has introduced process orientation at the printing company Color Print Sweden AB. The outcome ofthis work is a survey of the work flow at the prepress department. To visualise the production process at the companya comprehensive mapping of the main process, order-to-delivery, has been made. The work has detected a couple ofcritical elements in the existing process. These elements are the following: initial check of material delivered to the prepressdepartment as well as the control made of the plotter print-out, digital test print and plate. To guarantee the qualityof the prints it is very important that the work made in the prepress department is optimized. This survey can thereforebe used as a basis for continuous improvement in the processes at Color Print Sweden AB. This work has alsoresulted in a template that Color Print Sweden AB can use to design routine descriptions to ensure that specific worktasks are performed the right way by everyone and all the time.

Functionalization of dendrimers for improved gene delivery to mesenchymal stem cell

Disease, injury, and age problems compromise human quality of life and continuously motivate the search for new and more efficacious therapeutic approaches. The field of Tissue Regeneration and Engineering has greatly evolved over the last years, mainly due to the combination of the important advances verified in Biomaterials Science and Engineering with those of Cell and Molecular Biology. In particular, a new and promising area arose – Nanomedicine – that takes advantage of the extremely small size and especial chemical and physical properties of Nanomaterials, offering powerful tools for health improvement. Research on Stem Cells, the self-renewing progenitors of body tissues, is also challenging to the medical and scientific communities, being expectable the appearance of new and exciting stem cell-based therapies in the next years. The control of cell behavior (namely, of cell proliferation and differentiation) is of key importance in devising strategies for Tissue Regeneration and Engineering. Cytokines, growth factors, transcription factors and other signaling molecules, most of them proteins, have been identified and found to regulate and support tissue development and regeneration. However, the application of these molecules in long-term regenerative processes requires their continuous presence at high concentrations as they usually present short half-lives at physiological conditions and may be rapidly cleared from the body. Alternatively, genes encoding such proteins can be introduced inside cells and be expressed using cell’s machinery, allowing an extended and more sustained production of the protein of interest (gene therapy). Genetic engineering of stem cells is particularly attractive because of their self-renewal capability and differentiation potential. For Tissue Regeneration and Engineering purposes, the patient’s own stem cells can be genetically engineered in vitro and, after, introduced in the body (with or without a scaffold) where they will not only modulate the behavior of native cells (stem cell-mediated gene therapy), but also directly participate in tissue repair. Cells can be genetically engineered using viral and non-viral systems. Viruses, as a result of millions of years of evolution, are very effective for the delivery of genes in several types of cells, including cells from primary sources. However, the risks associated with their use (like infection and immunogenic reactions) are driving the search for non-viral systems that will efficiently deliver genetic material into cells. Among them, chemical methods that are promising and being investigated use cationic molecules as carriers for DNA. In this case, gene delivery and gene expression level remain relatively low when primary cells are used. The main goal of this thesis was to develop and assess the in vitro potential of polyamidoamine (PAMAM) dendrimers based carriers to deliver genes to mesenchymal stem cells (MSCs). PAMAM dendrimers are monodispersive, hyperbranched and nanospherical molecules presenting unique characteristics that make them very attractive vehicles for both drug and gene delivery. Although they have been explored for gene delivery in a wide range of cell lines, the interaction and the usefulness of these molecules in the delivery of genes to MSCs remains a field to be explored. Adult MSCs were chosen for the studies due to their potential biomedical applications (they are considered multipotent cells) and because they present several advantages over embryonic stem cells, such as easy accessibility and the inexistence of ethical restrictions to their use. This thesis is divided in 5 interconnected chapters. Chapter I provides an overview of the current literature concerning the various non-viral systems investigated for gene delivery in MSCs. Attention is devoted to physical methods, as well as to chemical methods that make use of polymers (natural and synthetic), liposomes, and inorganic nanoparticles as gene delivery vectors. Also, it summarizes the current applications of genetically engineered mesenchymal stem cells using non-viral systems in regenerative medicine, with special focus on bone tissue regeneration. In Chapter II, the potential of native PAMAM dendrimers with amine termini to transfect MSCs is evaluated. The level of transfection achieved with the dendrimers is, in a first step, studied using a plasmid DNA (pDNA) encoding for the β-galactosidase reporter gene. The effect of dendrimer’s generation, cell passage number, and N:P ratio (where N= number of primary amines in the dendrimer; P= number of phosphate groups in the pDNA backbone) on the level of transfection is evaluated, being the values always very low. In a second step, a pDNA encoding for bone morphogenetic protein-2, a protein that is known for its role in MSCs proliferation and differentiation, is used. The BMP-2 content produced by transfected cells is evaluated by an ELISA assay and its effect on the osteogenic markers is analyzed through several classical assays including alkaline phosphatase activity (an early marker of osteogenesis), osteocalcin production, calcium deposition and mineralized nodules formation (late osteogenesis markers). Results show that a low transfection level is enough to induce in vitro osteogenic differentiation in MSCs. Next, from Chapter III to Chapter V, studies are shown where several strategies are adopted to change the interaction of PAMAM dendrimers with MSCs cell membrane and, as a consequence, to enhance the levels of gene delivery. In Chapter III, generations 5 and 6 of PAMAM dendrimers are surface functionalized with arginine-glycine-aspartic acid (RGD) containing peptides – experiments with dendrimers conjugated to 4, 8 and 16 RGD units were performed. The underlying concept is that by including the RGD integrin-binding motif in the design of the vectors and by forming RGD clusters, the level of transfection will increase as MSCs highly express integrins at their surface. Results show that cellular uptake of functionalized dendrimers and gene expression is enhanced in comparison with the native dendrimers. Furthermore, gene expression is dependent on both the electrostatic interaction established between the dendrimer moiety and the cell surface and the nanocluster RGD density. In Chapter IV, a new family of gene delivery vectors is synthesized consisting of a PAMAM dendrimer (generation 5) core randomly linked at the periphery to alkyl hydrophobic chains that vary in length and number. Herein, the idea is to take advantage of both the cationic nature of the dendrimer and the capacity of lipids to interact with biological membranes. These new vectors show a remarkable capacity for internalizing pDNA, being this effect positively correlated with the –CH2– content present in the hydrophobic corona. Gene expression is also greatly enhanced using the new vectors but, in this case, the higher efficiency is shown by the vectors containing the smallest hydrophobic chains. Finally, chapter V reports the synthesis, characterization and evaluation of novel gene delivery vectors based on PAMAM dendrimers (generation 5) conjugated to peptides with high affinity for MSCs membrane binding - for comparison, experiments are also done with a peptide with low affinity binding properties. These systems present low cytotoxicity and transfection efficiencies superior to those of native dendrimers and partially degraded dendrimers (Superfect®, a commercial product). Furthermore, with this biomimetic approach, the process of gene delivery is shown to be cell surface receptor-mediated. Overall, results show the potential of PAMAM dendrimers to be used, as such or modified, in Tissue Regeneration and Engineering. To our knowledge, this is the first time that PAMAM dendrimers are studied as gene delivery vehicles in this context and using, as target, a cell type with clinical relevancy. It is shown that the cationic nature of PAMAM dendrimers with amine termini can be synergistically combined with surface engineering approaches, which will ultimately result in suitable interactions with the cytoplasmic membrane and enhanced pDNA cellular entry and gene expression. Nevertheless, the quantity of pDNA detected inside cell nucleus is always very small when compared with the bigger amount reaching cytoplasm (accumulation of pDNA is evident in the perinuclear region), suggesting that the main barrier to transfection is the nuclear membrane. Future work can then be envisaged based on the versatility of these systems as biomedical molecular materials, such as the conjugation of PAMAM dendrimers to molecules able to bind nuclear membrane receptors and to promote nuclear translocation.

Hypothermia and Early Neonatal Mortality in Preterm Infants

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)