Defining the Effect of the 16p11.2 Duplication on Cognition, Behavior, and Medical Comorbidities.

IMPORTANCE: The 16p11.2 BP4-BP5 duplication is the copy number variant most frequently associated with autism spectrum disorder (ASD), schizophrenia, and comorbidities such as decreased body mass index (BMI). OBJECTIVES: To characterize the effects of the 16p11.2 duplication on cognitive, behavioral, medical, and anthropometric traits and to understand the specificity of these effects by systematically comparing results in duplication carriers and reciprocal deletion carriers, who are also at risk for ASD. DESIGN, SETTING, AND PARTICIPANTS: This international cohort study of 1006 study participants compared 270 duplication carriers with their 102 intrafamilial control individuals, 390 reciprocal deletion carriers, and 244 deletion controls from European and North American cohorts. Data were collected from August 1, 2010, to May 31, 2015 and analyzed from January 1 to August 14, 2015. Linear mixed models were used to estimate the effect of the duplication and deletion on clinical traits by comparison with noncarrier relatives. MAIN OUTCOMES AND MEASURES: Findings on the Full-Scale IQ (FSIQ), Nonverbal IQ, and Verbal IQ; the presence of ASD or other DSM-IV diagnoses; BMI; head circumference; and medical data. RESULTS: Among the 1006 study participants, the duplication was associated with a mean FSIQ score that was lower by 26.3 points between proband carriers and noncarrier relatives and a lower mean FSIQ score (16.2-11.4 points) in nonproband carriers. The mean overall effect of the deletion was similar (-22.1 points; P < .001). However, broad variation in FSIQ was found, with a 19.4- and 2.0-fold increase in the proportion of FSIQ scores that were very low (≤40) and higher than the mean (>100) compared with the deletion group (P < .001). Parental FSIQ predicted part of this variation (approximately 36.0% in hereditary probands). Although the frequency of ASD was similar in deletion and duplication proband carriers (16.0% and 20.0%, respectively), the FSIQ was significantly lower (by 26.3 points) in the duplication probands with ASD. There also were lower head circumference and BMI measurements among duplication carriers, which is consistent with the findings of previous studies. CONCLUSIONS AND RELEVANCE: The mean effect of the duplication on cognition is similar to that of the reciprocal deletion, but the variance in the duplication is significantly higher, with severe and mild subgroups not observed with the deletion. These results suggest that additional genetic and familial factors contribute to this variability. Additional studies will be necessary to characterize the predictors of cognitive deficits.

Intoxication alcoolique aux urgences : dilemmes de prise en charge. Deux situations cliniques fréquentes. [The dilemma of defining "adequate" ED care for acute alcohol intoxication. About two case reports]

L'intoxication éthylique aiguë (IEA) est un motif de recours fréquent en médecine d'urgence. Bien qu'évoluant de manière spontanément favorable dans la majorité des cas, un certain nombre de complications sont susceptibles de survenir dans ce contexte, entrainant des répercussions significatives sur le pronostic des patients. Or, les altérations neurocomportementales accompagnant classiquement ce type d'intoxication mettent régulièrement les cliniciens face à des dilemmes de prise en charge complexes à résoudre. D'autre part, si les propriétés de l'éthanol peuvent atténuer l'expression clinique de certaines pathologies, un certain nombre d'affection de nature métabolique ou neurologique sont susceptibles d'être interprétées à tort comme des IEA. La littérature médicale ne fournissant que peu d'outils d'aide à la décision dans ce domaine, il est souvent difficile de trouver un compromis acceptable entre recours excessif aux examens complémentaires et banalisation face aux patients alcoolisés. A partir de situations cliniques, le présent article propose une approche pragmatique de deux problématiques régulièrement associées à une IEA et sources d'erreur diagnostique, le traumatisme crânien et l'état d'agitation. Ainsi, une meilleure définition des conditions de recours au scanner cérébral en cas de traumatisme crânien et l'adoption d'un protocole de sédation précoce dans l'ivresse excito-motrice doivent permettre de contourner en partie les difficultés soulevées par ces patients.

Combining Customer Requirements and Modularity in Complete Tap Water Solution

This thesis studies forming a complete solution concept for tap water systems in project business environment. The aim of the study is to find tools and means for the target company to determine the scope of their tap water solution offering and to research what kind of organizational capabilities and resources are needed to supply such system solutions. With the help of literature, the characteristics of systems selling and project business and thematics of systems integration and integrated solutions are examined, and the significance of modularity and customer requirements in the given operational environment is discussed. After this, a checklist tool for customer requirements management is developed for the tap water system along with a module allocation method. The study proposes that with the checklist and module allocation the technical specifications can be extensively and innovatively defined for the system. The tools developed are a part of a complete tap water solution concept, which suggests that integrated solutions might constitute possibilities for the company to outperform its competitors when the traditional business methods of the industry are becoming obsolete.

Defining a framework model to determine total costs of managed desktops using ITIL best practices

In modern day organizations there are an increasing number of IT devices such as computers, mobile phones and printers. These devices can be located and maintained by using specialized IT management applications. Costs related to a single device accumulate from various sources and are normally categorized as direct costs like hardware costs and indirect costs such as labor costs. These costs can be saved in a configuration management database and presented to users using web based development tools such as ASP.NET. The overall costs of IT devices during their lifecycle can be ten times higher than the actual purchase price of the product and ability to define and reduce these costs can save organizations noticeable amount of money. This Master’s Thesis introduces the research field of IT management and defines a custom framework model based on Information Technology Infrastructure Library (ITIL) best practices which is designed to be implemented as part of an existing IT management application for defining and presenting IT costs.

Contribution of cytochrome P450 and ABCB1 genetic variability on methadone pharmacokinetics, dose requirements, and response

Although the efficacy of methadone maintenance treatment (MMT) in opioid dependence disorder has been well established, the influence of methadone pharmacokinetics in dose requirement and clinical outcome remains controversial. The aim of this study is to analyze methadone dosage in responder and nonresponder patients considering pharmacogenetic and pharmacokinetic factors that may contribute to dosage adequacy. Opioid dependence patients (meeting Diagnostic and Statistical Manual of Mental Disorders, [4th Edition] criteria) from a MMT community program were recruited. Patients were clinically assessed and blood samples were obtained to determine plasma concentrations of (R,S)-, (R) and (S)- methadone and to study allelic variants of genes encoding CYP3A5, CYP2D6, CYP2B6, CYP2C9, CYP2C19, and P-glycoprotein. Responders and nonresponders were defined by illicit opioid consumption detected in random urinalysis. The final sample consisted in 105 opioid dependent patients of Caucasian origin. Responder patients received higher doses of methadone and have been included into treatment for a longer period. No differences were found in terms of genotype frequencies between groups. Only CYP2D6 metabolizing phenotype differences were found in outcome status, methadone dose requirements, and plasma concentrations, being higher in the ultrarapid metabolizers. No other differences were found between phenotype and responder status, methadone dose requirements, neither in methadone plasma concentrations. Pharmacokinetic factors could explain some but not all differences in MMT outcome and methadone dose requirements.

Defining housing market areas using commuting and migration algorithms. Catalonia (Spain) as an applied case study

In the literature on housing market areas, different approaches can be found to defining them, for example, using travel-to-work areas and, more recently, making use of migration data. Here we propose a simple exercise to shed light on which approach performs better. Using regional data from Catalonia, Spain, we have computed housing market areas with both commuting data and migration data. In order to decide which procedure shows superior performance, we have looked at uniformity of prices within areas. The main finding is that commuting algorithms present more homogeneous areas in terms of housing prices.

Improving Evaluation and Development Capability in Verification and Validation

Validation and verification operations encounter various challenges in product development process. Requirements for increasing the development cycle pace set new requests for component development process. Verification and validation usually represent the largest activities, up to 40 50 % of R&D resources utilized. This research studies validation and verification as part of case company's component development process. The target is to define framework that can be used in improvement of the validation and verification capability evaluation and development in display module development projects. Validation and verification definition and background is studied in this research. Additionally, theories such as project management, system, organisational learning and causality is studied. Framework and key findings of this research are presented. Feedback system according of the framework is defined and implemented to the case company. This research is divided to the theory and empirical parts. Theory part is conducted in literature review. Empirical part is done in case study. Constructive methode and design research methode are used in this research A framework for capability evaluation and development was defined and developed as result of this research. Key findings of this study were that double loop learning approach with validation and verification V+ model enables defining a feedback reporting solution. Additional results, some minor changes in validation and verification process were proposed. There are a few concerns expressed on the results on validity and reliability of this study. The most important one was the selected research method and the selected model itself. The final state can be normative, the researcher may set study results before the actual study and in the initial state, the researcher may describe expectations for the study. Finally reliability of this study, and validity of this work are studied.

Explosion-proof requirements for Electrical Machines in Chemical, Oil and Gas Industry in Russia and CIS Countries

One of the main industries which form the basis of Russian Economical structure is oil and gas. This industry is also playing a significant role for CIS countries. Oil and gas industry is developing intensively attracting foreign investments. This situation is providing sustainable development of machinery production for hazardous areas. Operating in oil and gas areas is always related with occurrence of explosion gas atmospheres. Machines for hazardous areas must be furnished with additional protection of different types. Explosion protection is regulated with standards according to which equipment must be manufactured. In Russia and CIS countries explosion-proof equipment must be constructed in compliance with GOST standards. To confirm that equipment is manufactured according to standards’ requirements and is safe and reliable it must undergo the approval procedure. Certification in Russia is governed by Federal Laws and legislation. Each CIS country has its own approval certificates and permissions for operating in hazardous areas.

Methods for assessing the sustainability of integrated municipal waste management and

The general striving to bring down the number of municipal landfills and to increase the reuse and recycling of waste-derived materials across the EU supports the debates concerning the feasibility and rationality of waste management systems. Substantial decrease in the volume and mass of landfill-disposed waste flows can be achieved by directing suitable waste fractions to energy recovery. Global fossil energy supplies are becoming more and more valuable and expensive energy sources for the mankind, and efforts to save fossil fuels have been made. Waste-derived fuels offer one potential partial solution to two different problems. First, waste that cannot be feasibly re-used or recycled is utilized in the energy conversion process according to EU’s Waste Hierarchy. Second, fossil fuels can be saved for other purposes than energy, mainly as transport fuels. This thesis presents the principles of assessing the most sustainable system solution for an integrated municipal waste management and energy system. The assessment process includes: · formation of a SISMan (Simple Integrated System Management) model of an integrated system including mass, energy and financial flows, and · formation of a MEFLO (Mass, Energy, Financial, Legislational, Other decisionsupport data) decision matrix according to the selected decision criteria, including essential and optional decision criteria. The methods are described and theoretical examples of the utilization of the methods are presented in the thesis. The assessment process involves the selection of different system alternatives (process alternatives for treatment of different waste fractions) and comparison between the alternatives. The first of the two novelty values of the utilization of the presented methods is the perspective selected for the formation of the SISMan model. Normally waste management and energy systems are operated separately according to the targets and principles set for each system. In the thesis the waste management and energy supply systems are considered as one larger integrated system with one primary target of serving the customers, i.e. citizens, as efficiently as possible in the spirit of sustainable development, including the following requirements: · reasonable overall costs, including waste management costs and energy costs; · minimum environmental burdens caused by the integrated waste management and energy system, taking into account the requirement above; and · social acceptance of the selected waste treatment and energy production methods. The integrated waste management and energy system is described by forming a SISMan model including three different flows of the system: energy, mass and financial flows. By defining the three types of flows for an integrated system, the selected factor results needed in the decision-making process of the selection of waste management treatment processes for different waste fractions can be calculated. The model and its results form a transparent description of the integrated system under discussion. The MEFLO decision matrix has been formed from the results of the SISMan model, combined with additional data, including e.g. environmental restrictions and regional aspects. System alternatives which do not meet the requirements set by legislation can be deleted from the comparisons before any closer numerical considerations. The second novelty value of this thesis is the three-level ranking method for combining the factor results of the MEFLO decision matrix. As a result of the MEFLO decision matrix, a transparent ranking of different system alternatives, including selection of treatment processes for different waste fractions, is achieved. SISMan and MEFLO are methods meant to be utilized in municipal decision-making processes concerning waste management and energy supply as simple, transparent and easyto- understand tools. The methods can be utilized in the assessment of existing systems, and particularly in the planning processes of future regional integrated systems. The principles of SISMan and MEFLO can be utilized also in other environments, where synergies of integrating two (or more) systems can be obtained. The SISMan flow model and the MEFLO decision matrix can be formed with or without any applicable commercial or free-of-charge tool/software. SISMan and MEFLO are not bound to any libraries or data-bases including process information, such as different emission data libraries utilized in life cycle assessments.

Yrityksen strategiaprosessi : Näkökulmia strategisen johtamisen kehitämiseksi konserniorganisaatiossa

Tämän tutkimuksen tavoitteena oli määritellä strategiaprosessiin liittyvät kriittiset alueet, konsernijohdon tehtävät strategiaprosessissa sekä edellisten pohjalta kehittää konsernityyppiselle yritykselle normatiivinen strategiaprosessin malli kriittisten alueiden hallitsemiseksi. Tavoitteena oli myös lisätä strategisen ajattelun ja strategiaprosessien ymmärtämistä selittämällä niiden historiallista kehittymistä sekä niiden käsitteistöä ja käsitteiden sisältöä. Probleemaa lähestyttiin sekä doktriinin kautta että tulkitsemalla strategiaprosessissa ilmeneviä ongelmia ja analysoimalla niiden syy ja seuraussuhteita. Käsillä oleva teoreettis praktinen tutkimus toteutettiin osittain toiminta-analyyttisella tutkimusotteella, osittain toiminta analyyttisella tutkimusotteella case tutkimuksen ja komparatiivisen analyysin tukemana sekä osittain päätöksentekometodologisella tutkimusotteella. Työn teoreettinen osa tehtiin kirjallisuustutkimuksena. Siinä luotiin strategiaprosessin ja konsernijohtamisen käsitteellinen perusta ja tutkimuksen viitekehys. Konsernijohtaminen laajennettiin tutkimuksessa tulosten osalta yleistäen koskemaan muitakin hajautettuja yritysorganisaatioita kuin pelkän juridiikan pohjalta muodostuneita konserneja. Tutkimuksen aluksi tarkasteltiin strategisen ajattelun koulukuntia eri näkemyksineen sekä toisaalta strategia-ajattelun kehittymistrendeja 1950 luvulta nykyhetkeen. Samoin tarkasteltiin sitä, kuinka strategiaprosessit oval kehittyneet samara ajanjaksona. Huomion painopisteen todettiin siirtyneen strategisen johtamisen inhimilliseen puoleen strategisem johtajuuden samalla korostuessa ja strategisen ajattelun laajentuessa Empiirinen osuus toteutettiin case tutkimuksena. Sen kuluessa kartoitettiin strategiaprosessin keskeiset ongelma alueet ja analysoitiin niiden takana olevat syyt, jotta voidin määritellä strategiapmsessin kehittämisen suunnat ja painopisteaiueet. Teoreettisen ja empiirisen osan penisteella määriteltiin strategiaprosessin kriittiset alueet yleisellä tasolla. Kriittisellä alueella tarkoitetaan asiakokonaisuutta tai asiaa, jonka on oltava kunaossa, jotta strategiaprosessit toimisivat. Nämä alueet liittyvat itse strategiaprosessiin suoraan tai välillisesti muun johtamistyön kautta. Strategiaprosessin kriittisten alueiden määrittelyn yhteydessä asetettiin doktriiniin tukeutuen strategiaprosessin kehittämissuunnat konsernijohdon nakäkökulmasta tarkasteltuna. Näihin kehittämissuuntiin ja edelleen doktriiniin tukeutuen määriteltiin konsernijohdon strategiaprosessin substanssitehtävät, prosessia tukevat tehtävät sekä prosessin toteuttamis- ja kehittämistehtävtä. Konsernijohdon strategiaprosessin tehtävät eivät muodosta sekventiaalista ja hierarkista järjestelmää vaan ovat joukko aktiviteetteja, joita toteutetaan tarpeen mukaan. Konsernijohdon strategiaprosessi määriteltiin ja kuvattiin tutkimuksessa johdon työskentelyprosessiksi sellaisten toimeenpanokelpoisten strategioiden tuottamiseksi ja toimeenpanemiseksi, jotka lisäävät yrityksen (konsernin) arvoa omistajan näkökulmasta mutta huomioivat myös muiden keskeisten sidosryhmien vaatimukset, tavoitteet ja rajoitteet. Konsernijohdon strategiaprosessi nähdään tässä jatkuvana konsernitasoisena päämäärä- ja keinopuolen tarkasteluna. Siinä konsernijohto tiedostaa konsernin ulkoisesta ja sisäisestä ymparistostä tulevat signaalit sekä pitää yllä näkemystä konsernin strategisesta asemasta. Tiedon massan näkemyksen saavutettua kriittisen rajansa se pakottaa konsernijohdon aivioimaan aiempia ratkaisuja uudessa valossa. Tämä validointi perustuu jatkuvasti esitettyihin neljään kysymykseen: onko ympäristö , premissi ja toimeenpanoseurannasta kertyneen tietämyksen perusteella nähtävissä vaikutuksia välittömiin toimenpiteisiin, vaikutuksia toimintasuunnitelmiin tai kriittisiin seurannan kohteisiin, vaikutuksia suunnanvalintoihin tai vaikutuksia perususkomuksiin? Konsernijohdon strategiaprosessi etenee jatkuvana prosessina päätösten ja ajan virrassa.

Tuotannonohjauksen kehittäminen piensarjatuotannossa

Tämä diplomityö käsittelee teollisen yrityksen tuotannonohjauksen kehittämistä piensarjatuotannossa. Työn kohteena on ABB Oy:n Tuulivoimageneraattorit-tulosyksikkö, joka valmistaa vakiotuotteita asiakasohjautuvasti. Työssä esitellään aluksi tuotannon ja tuotannonohjauksen teoriaa. Lävitse käydään perusasioiden kuten määritelmien, tavoitteiden ja tehtävien lisäksi tuotannonohjausprosessia sekä tuotannonohjauksen tietotekniikkaa. Teorian jälkeisessä empiriaosuudessa esitellään työssä kehitettyjä keinoja tuotannonohjauksen parantamiseksi. Tutkimus on toteutettu teoreettisen ja empiirisen tutkimustyön avulla. Teoreettiseen tutkimustyöhön sisältyi suomalaisiin ja ulkomaalaisiin kirjallisuuslähteisiin perehtyminen. Empiirinen tutkimustyö suoritettiin itsenäisen ongelman ratkaisutyön avulla. Tämä sisälsi kehittämiskohteiden analysoinnin, tarkempien kehittämistarpeiden määrityksen sekä kokeilujen kautta tapahtuneen kehittämistyön. Tutkimuksen päätavoitteena oli selvittää, miten tuotannonohjauksen kehittämisellä voidaan parantaa kohteena olevan tulosyksikön tuottavuutta ja kannattavuutta. Päätavoitteen pohjalta muodostettiin kuusi osatavoitetta: toimitusvarmuuden parantaminen, kapasiteetin kuormitusasteen nostaminen, kapasiteetin suunnittelun kehittäminen, läpäisyaikojen lyhentäminen, uuden ERP-järjestelmän vaatimusmäärittely sekä tuotannonohjausprosessin määrittäminen. Työssä rakennettiin neljään ensiksi mainittuun osatavoitteeseen tietotekniset sovellukset, jotka mahdollistavat osatavoitteiden suunnittelun ja ohjaamisen. Sovelluksia varten kullekin tuotteelle määriteltiin esimerkiksi työnvaiheketjut läpäisyaikoineen, kuormitusryhmät, kuormitusryhmien kapasiteetit, tuotteiden kuormittavuudet sekä kriittiset työvälineet. Työ osoitti, että tietotekniikka auttaa suuresti tuotannonohjauksessa. Lisääntynyt läpinäkyvyys, parantunut tiedonkulku, simulointimahdollisuudet sekä graafinen esitystapa helpottavat erilaisten suunnitelmien teossa ja parantavat siten päätöksenteon laatua. Tietotekniikan hyväksikäytön pohjana toimii tuotannon perus- ja tapahtumatietojen kurinalainen päivitys. Tämän vuoksi tietojärjestelmistä kannattaa rakentaa mahdollisimman yksinkertaisia.