A proposed framework for the systematic review and integrated assessment (SYRINA) of endocrine disrupting chemicals

Background - The issue of endocrine disrupting chemicals (EDCs) is receiving wide attention from both the scientific and regulatory communities. Recent analyses of the EDC literature have been criticized for failing to use transparent and objective approaches to draw conclusions about the strength of evidence linking EDC exposures to adverse health or environmental outcomes. Systematic review methodologies are ideal for addressing this issue as they provide transparent and consistent approaches to study selection and evaluation. Objective methods are needed for integrating the multiple streams of evidence (epidemiology, wildlife, laboratory animal, in vitro, and in silico data) that are relevant in assessing EDCs. Methods - We have developed a framework for the systematic review and integrated assessment (SYRINA) of EDC studies. The framework was designed for use with the International Program on Chemical Safety (IPCS) and World Health Organization (WHO) definition of an EDC, which requires appraisal of evidence regarding 1) association between exposure and an adverse effect, 2) association between exposure and endocrine disrupting activity, and 3) a plausible link between the adverse effect and the endocrine disrupting activity. Results - Building from existing methodologies for evaluating and synthesizing evidence, the SYRINA framework includes seven steps: 1) Formulate the problem; 2) Develop the review protocol; 3) Identify relevant evidence; 4) Evaluate evidence from individual studies; 5) Summarize and evaluate each stream of evidence; 6) Integrate evidence across all streams; 7) Draw conclusions, make recommendations, and evaluate uncertainties. The proposed method is tailored to the IPCS/WHO definition of an EDC but offers flexibility for use in the context of other definitions of EDCs. Conclusions - When using the SYRINA framework, the overall objective is to provide the evidence base needed to support decision making, including any action to avoid/minimise potential adverse effects of exposures. This framework allows for the evaluation and synthesis of evidence from multiple evidence streams. Finally, a decision regarding regulatory action is not only dependent on the strength of evidence, but also the consequences of action/inaction, e.g. limited or weak evidence may be sufficient to justify action if consequences are serious or irreversible.The workshops that supported the writing of this manuscript were funded by the Swedish Foundation for Strategic Environmental Research “Mistra”. LNV was funded by Award Number K22ES025811 from the National Institute of Environmental Health Sciences of the National Institutes of Health. TJW was funded by The Clarence Heller Foundation (A123547), the Passport Foundation, the Forsythia Foundation, the National Institute of Environmental Health Sciences (grants ES018135 and ESO22841), and U.S. EPA STAR grants (RD83467801 and RD83543301). JT was funded by the Academy of Finland and Sigrid Juselius. UH was funded by the Danish EPA. KAK was funded by the Canada Research Chairs program grant number 950–230607

Novel genetic loci underlying human intracranial volume identified through genome-wide association

Intracranial volume reflects the maximally attained brain size during development, and remains stable with loss of tissue in late life. It is highly heritable, but the underlying genes remain largely undetermined. In a genome-wide association study of 32,438 adults, we discovered five novel loci for intracranial volume and confirmed two known signals. Four of the loci are also associated with adult human stature, but these remained associated with intracranial volume after adjusting for height. We found a high genetic correlation with child head circumference (ρgenetic=0.748), which indicated a similar genetic background and allowed for the identification of four additional loci through meta-analysis (Ncombined = 37,345). Variants for intracranial volume were also related to childhood and adult cognitive function, Parkinson’s disease, and enriched near genes involved in growth pathways including PI3K–AKT signaling. These findings identify biological underpinnings of intracranial volume and provide genetic support for theories on brain reserve and brain overgrowth

Genetic mechanisms of critical illness in COVID-19.

Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P = 1.65 × 10-8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 × 10-8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 ×  10-12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 × 10-8) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte-macrophage chemotactic receptor CCR2 is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice

Novel genetic loci associated with hippocampal volume

The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel. Of the novel loci, three lie within genes (ASTN2, DPP4 and MAST4) and one is found 200 kb upstream of SHH. A hippocampal subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippocampal volume are also associated with increased risk for Alzheimer's disease (rg =-0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippocampal volume and risk for neuropsychiatric illness

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

PALVELUTUOTTEEN HINNOITTELUN KEHITTÄMINEN

Tämän opinnäytetyön aiheena on palvelutuotteen hinnoittelun kehittäminen. Tutkimuksen kohteena on Tili- ja isännöitsijätoimisto Ky. Tili- ja isännöitsijätoimisto Ky on Vaasassa toimiva tili- ja isännöintitoimisto, joka tarjoaa taloushallinto- ja isännöintipalveluita yrityksille. Tutkimuksen tavoitteena on kehittää Tili- ja isännöitsijätoimisto Ky:n isännöitsijän palvelutuotteiden hinnoittelua. Hinnoittelumenetelmäksi valittiin toimintoperusteinen hinnoittelu, jonka lähtökohtana on selvittää asiakaskohtaisia välillisiä kustannuksia. Kysymys oli suorite-kohtaisten kustannusten laskemisesta, eli toimintoperusteisesta prosessilaskennasta. Toimintoperusteinen prosessilaskenta tukee hinnoittelun päätöstä. Toiminto-analyysin jälkeen selvitettiin resurssien kohdistumista yrityksen eri toiminnoille. Aluksi selvitettiin yrityksen kustannusajuri, jonka perusteella kustannukset on kohdistettu eri toiminnoille. Seuraavaksi selvitettiin toimintoajurin avulla toimintoihin liittyvät yksikkökustannukset. Tuotteiden hinnoittelussa myyntihinnan on tarkoituksena sisältää kaikkien kustannusten lisäksi voittotavoite. Tutkimuksen teoriaosuuden keskeisiä asioita ovat toimintoperusteisen kustannuslaskennan, sekä hinnoittelun perusteiden esittely. Niiden avulla voidaan perustella hinnoittelupäätöstä tukeva toimintolaskenta. Opinnäytetyössä esitellään lisäksi kustannusperusteista hinnoittelua sekä isännöintiä ja tilitoimistoa yleisesti. Tutkimusmenetelmänä käytettiin kvalitatiivista eli laadullista tutkimusta. Tutkimuksen teoriaosuuteen käytettiin toimintolaskennan, taloushallinnon alan sekä hinnoittelun teoriaan liittyvää kirjallisuutta. Aineistonkeruussa havainnoitiin yrityksen tilinpäätöstä vuodelta 2016 ja yrityksen toimintaa liittyviä ohjelmia sekä tietokantoja. Lisäksi haastateltiin Tili- ja isännöitsijätoimisto Ky:n omistajaa ja työntekijöitä.This research was designed to develop the used pricing method for the case firm Tili- ja isännöitsijätoimisto Ky. The main area of this research focused on the main service products in property management. The case firm offers financial accounting and management services to house companies and other customer companies. Activity based costing was selected as the new pricing method in order to identify the customer-specific indirect costs. The aim of activity-based costing was to support pricing decisions for the case firm. In the implementation steps, activities must be identified first, and then the process continues with an activity analysis. Once the costs of activity and its drivers have been identified and its costs have been determined, then the costs of activity is allocated to the service product. In the allocation process, when the activity driver has been determined, the cost per unit can then be determined. Once the product cost per unit has been determined then the case firm considers the generated value of its service product, so the pricing of all the service product sales cover the fixed expenses with any remaining contribution margin providing profits. The theoretical study of this thesis introduced activity based costing and pricing to support activity based cost implementation and pricing decisions. In addition, it introduced cost based pricing and property management business and accounting firms in general. This research was implemented using the qualitative research method. The research material consists of related activity based costing, financial management, management accounting and pricing literature. The theoretical information was gathered from scientific research, academic books and some material was collect-ed from the Internet. The empirical data in this research was gathered by observing the case company’s financial statement from the year 2016 together with some business activities related programs and databases. In addition, was collected by interviewing the case company owner and the other employers of the company