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Background: Assessing detailed metabolism in exercising persons minute-to-minute has not been possible. We developed a “drop-of-blood” platform to fulfill that need. Our study aimed not only to demonstrate the utility of our methodology, but also to give insights into unknown mechanisms and new directions.Methods: We developed a platform, based on gas chromatography and mass spectrometry, to assess metabolism from a blood-drop. We first observed a single volunteer who ran 13 km in 61 min. We particularly monitored relative perceived exertion (RPE). We observed that 2,3-bisphosphoglycerate peaked at RPE in this subject. We next expanded these findings to women and men volunteers who performed an RPE-based exercise protocol to RPE at Fi O 2 20.9% or Fi O 2 14.5% in random order.Results: At 6 km, our subject reached his maximum relative perceived exertion (RPE); however, he continued running, felt better, and finished his run. Lactate levels had stably increased by 2 km, ketoacids increased gradually until the run’s end, while the hypoxia marker, 2,3 bisphosphoglycerate, peaked at maximum relative perceived exertion. In our normal volunteers, the changes in lactate, pyruvate, ß hydroxybutyrate and a hydroxybutyrate were not identical, but similar to our model proband runner.Conclusion: Glucose availability was not the limiting factor, as glucose availability increased towards exercise end in highly exerted subjects. Instead, the tricarboxylic acid→oxphos pathway, lactate clearance, and thus and the oxidative capacity appeared to be the defining elements in confronting maximal exertion. These ideas must be tested further in more definitive studies. Our preliminary work suggests that our single-drop methodology could be of great utility in studying exercise physiology.

Extracorporeal support systems for the heart and lungs are employed for cardiac, pulmonary and also cardiopulmonary failure; however, neither the pure lung support by venovenous extracorporeal membrane oxygenation (vvECMO) nor the venoarterial (va) ECMO behave in a hemodynamically inert manner with respect to the patient's own cardiovascular system. The success of ECMO treatment is decisively dependent on monitoring before and during the execution and the pathophysiological understanding of the hemodynamic changes that occur during treatment. This article explicitly elucidates these "concomitant phenomena" and discusses fundamental aspects of cardiovascular physiology and the specific interplay with ECMO treatment.Extrakorporale Unterstützungssysteme von Herz und Lunge werden bei kardialem, pulmonalem oder auch kardiopulmonalem Versagen eingesetzt. Jedoch verhält sich weder die rein lungenunterstützende venovenöse extrakorporale Membranoxygenierung (vv-ECMO) noch die venoarterielle (va‑)ECMO hämodynamisch „inert“ gegenüber dem patienteneigenen Herz-Kreislauf-System. Der Erfolg einer ECMO-Therapie hängt entscheidend vom Monitoring vor und während der Durchführung sowie dem pathophysiologischen Verständnis für die hämodynamischen Veränderungen, die während der Therapie auftreten, ab. Der vorliegende Beitrag erläutert gezielt diese „Begleiterscheinungen“ und diskutiert fundamentale Aspekte der Herz-Kreislauf-Physiologie und ihr spezifisches Zusammenspiel mit einer ECMO-Therapie.

The study of eye movements in programming has many implications to software engineering and computing education in industry and academia. The 10th International Workshop on Eye Movements in Programming (EMIP 2022) was co-located with the 44th International Conference on Software Engineering (ICSE), with the goal to further develop the methodology of using eye tracking for programming and software engineering, both theoretically and in practice.

We investigated the heritability of educational attainment and how it differed between birth cohorts and cultural-geographic regions. A classical twin design was applied to pooled data from 28 cohorts representing 16 countries and including 193,518 twins with information on educational attainment at 25 years of age or older. Genetic factors explained the major part of individual differences in educational attainment (heritability: a(2)=0.43; 0.41-0.44), but also environmental variation shared by co-twins was substantial (c(2)=0.31; 0.30-0.33). The proportions of educational variation explained by genetic and shared environmental factors did not differ between Europe, North America and Australia, and East Asia. When restricted to twins 30 years or older to confirm finalized education, the heritability was higher in the older cohorts born in 1900-1949 (a(2)=0.44; 0.41-0.46) than in the later cohorts born in 1950-1989 (a(2)=0.38; 0.36-0.40), with a corresponding lower influence of common environmental factors (c(2)=0.31; 0.29-0.33 and c(2)=0.34; 0.32-0.36, respectively). In conclusion, both genetic and environmental factors shared by co-twins have an important influence on individual differences in educational attainment. The effect of genetic factors on educational attainment has decreased from the cohorts born before to those born after the 1950s. This study was conducted within the CODATwins project. We thank Wendy Cozen, University of Southern California, for sharing data with us. Funding for collaborators: Netherlands Twin Register acknowledges the Netherlands Organization for Scientific Research (NWO) and MagW/ZonMW grants 904-61-090, 985-10-002, 912-10-020, 904-61-193,480-04-004, 463-06-001, 451-04-034, 400-05-717, Addiction-31160008, Middelgroot-911-09-032, Spinozapremie 56-464-14192; VU University's Institute for Health and Care Research (EMGO+); the European Research Council (ERC - 230374), the Avera Institute, Sioux Falls, South Dakota (USA). Data collection and analyses in Finnish twin cohorts have been supported by ENGAGE - European Network for Genetic and Genomic Epidemiology, FP7-HEALTH-F4-2007, Grant Agreement Number 201413, National Institute of Alcohol Abuse and Alcoholism (Grants AA-12502, AA-00145, and AA-09203 to R J Rose, the Academy of Finland Center of Excellence in Complex Disease Genetics (Grant Numbers: 213506, 129680), and the Academy of Finland (Grants 100499, 205585, 118555, 141054, 265240, 263278 and 264146 to J Kaprio). Since its origin the East Flanders Prospective Survey has been partly supported by grants from the Fund of Scientific Research, Flanders and Twins, a non-profit Association for Scientific Research in Multiple Births (Belgium). Anthropometric measurements of the Hungarian twins were supported by Medexpert Ltd., Budapest, Hungary. The Murcia Twin Registry is supported by Fundacion Seneca, Regional Agency for Science and Technology, Murcia, Spain (08633/PHCS/08, 15302/PHCS/10 & 19479/PI/14) and Ministry of Science and Innovation, Spain (PSI2009-11560 & PSI2014-56680-R). K Silventoinen is supported by Osaka University's International Joint Research Promotion Program. We acknowledge The Swedish Twin Registry for access to data. The Swedish Twin Registry is managed by Karolinska Institutet and receives funding through the Swedish Research Council under the grant no 2017-00641. This research was facilitated through access to Twins Research Australia, a national resource supported by a Centre of Research Excellence Grant (ID: 1079102), from the National Health and Medical Research Council. California Twin Program was supported by The California Tobacco-Related Disease Research Program (7RT-0134H, 8RT-0107H, 6RT-0354H) and the National Institutes of Health (1R01ESO15150-01). The Carolina African American Twin Study of Aging (CAATSA) was funded by a grant from the National Institute on Aging (grant 1RO1-AG13662-01A2) to K. E. Whitfield. Colorado Twin Registry is funded by NIDA funded center grant DA011015, & Longititudinal Twin Study HD10333; Author Huibregtse is supported by 5T32DA017637 and 5T32AG052371. Washington State Twin Registry (formerly the University of Washington Twin Registry) was supported in part by grant NIH RC2 HL103416 (D. Buchwald, PI). Vietnam Era Twin Study of Aging was supported by National Institute of Health grants NIA R01 AG018384, R01 AG018386, R01 AG022381, and R01 AG022982, and, in part, with resources of the VA San Diego Center of Excellence for Stress and Mental Health. The Cooperative Studies Program of the Office of Research & Development of the United States Department of Veterans Affairs has provided financial support for the development and maintenance of the Vietnam Era Twin (VET) Registry. The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the NIA/NIH, or the VA. The NAS-NRC Twin Registry acknowledges financial support from the National Institutes of Health grant number R21 AG039572. Korean Twin-Family Register was supported by the Global Research Network Program of the National Research Foundation (NRF 2011-220-E00006). Osaka University Aged Twin Registry is supported by grants from JSPS KAKENHI JP (23593419, 24792601, 26671010, 24590695, 26293128, 16K15385, 16K15978, 16K15989, 16H03261).

This retrospective real-world study investigated the clinical use of the sFlt-1 (soluble fms-like tyrosine kinase 1)/PlGF (placental growth factor) ratio alone or in combination with other clinical tests to predict an adverse maternal (maternal death, kidney failure, hemolysis elevated liver enzymes low platelets-syndrome, pulmonary edema, disseminated intravascular coagulation, cerebral hemorrhage, or eclampsia) or fetal (delivery before 34 weeks because of preeclampsia and/or intrauterine growth restriction, respiratory distress syndrome, necrotizing enterocolitis, intraventricular hemorrhage, placental abruption or intrauterine fetal death or neonatal death within 7 days post natum) pregnancy outcome in patients with signs and symptoms of preeclampsia. We evaluated the sFlt-1/PlGF-ratio cutoff values of 38 and 85 and evaluated its integration into a multimarker model. Of 1117 subjects, 322 (28.8%) developed an adverse fetal or maternal outcome. Patients with an adverse versus no adverse outcome had a median sFlt-1/PlGF-ratio of 177 (interquartile range, 54–362) versus 14 (4–64). Risk-stratification with the sFlt-1/PlGF cutoff values into high- (>85), intermediate- (38–85), and low-risk (

Several studies show an association of maternal diabetes during pregnancy with adverse offspring metabolic health. Other studies, however, suggest that this effect might be biased by obesity, which is independently associated with offspring metabolic disease and often coexistent to maternal diabetes. We performed a prospective study in a rat model to test the hypothesis that the burden of a diabetic pregnancy without obesity deteriorates metabolic health in male offspring. We generated maternal type 2 diabetes before conception that persisted during pregnancy by knockdown of the insulin receptor in small hairpin RNA–expressing transgenic rats. Male WT (wild type) offspring were followed up until adulthood and metabolically challenged by high-fat diet. Blood glucose was measured continuously via a telemetry device. Glucose and insulin tolerance tests were performed, and body composition was analyzed. Weight gain and glucose levels during adolescence and adulthood were similar in male offspring of diabetic and control pregnancies. Body weight and fat mass after high-fat diet, as well as glucose and insulin tolerance tests, were unaltered between male adult offspring of both groups. Glycemic control consisting of up to 49 000 individual glucose measures was comparable between both groups. Intrauterine exposure to maternal hyperglycemia and hyperinsulinemia without obesity had no impact on male offspring metabolic health in our model. We conclude that the intrauterine exposure itself does not represent a mechanism for fetal programming of diabetes and obesity in our model. Other maternal metabolic parameters during pregnancy, such as obesity, might impact long-term offspring metabolic health.

CD36 transports fatty acids (FA) into adipocytes and is increased in white adipose tissue (WAT) in obesity. In rodents, however, it was shown that CD36 knock out is protective for diet induced adiposity. In humans a hypocaloric high fat diet decreased CD36 gene expression in WAT. This study investigated the response of gene expression of FA uptake and metabolism in sub cutaneous WAT after a sudden switch from a healthy isocaloric low fat diet to an isocaloric high fat diet (HF) in healthy human twins. 35 monzyogotic and dizygotic healthy pairs of twins (women and men, age 18 - 70) were investigated for 12 weeks. An isocaloric diet rich in carbohydrates (55% carbohydrates, 30% fat, 15% protein, LF) was applied for 6 weeks, followed by an isocaloric diet rich in saturated fat (40% carbohydrates, 45% fat, 15% protein, HF) for another 6 weeks. Body weight (BW) , BMI, serum FA and gene expression of CD36, PDK4, PGC1α and CPT1α by qPCR were analyzed after the LF period, after one week (HF1) and at the end (HF6) of the HF period. BW did not change during the study. Serum FA were unchanged at HF1 but decreased at HF6 by 18% (P Disclosure M.Kruse: None. A.Ost: None. S.Hornemann: None. D.Hoffmann: None. T.Frahnow: None. A.Busjahn: None. A.F.Pfeiffer: None. Funding German Federal Ministry of Education and Research (0315424)

Background: The dysfunction of energy metabolism in white adipose tissue (WAT) induces adiposity. Obesogenic diets that are high in saturated fat disturb nutrient metabolism in adipocytes. This study investigated the effect of an isocaloric high-fat diet without the confounding effects of weight gain on the gene expression of fatty acid and carbohydrate transport and metabolism and its genetic inheritance in subcutaneous (s.c.) WAT of healthy human twins. Methods: Forty-six healthy pairs of twins (34 monozygotic, 12 dizygotic) received an isocaloric carbohydrate-rich diet (55% carbohydrates, 30% fat, 15% protein; LF) for 6 weeks followed by an isocaloric diet rich in saturated fat (40% carbohydrates, 45% fat, 15% protein; HF) for another 6 weeks. Results: Gene expression analysis of s.c. WAT revealed that fatty acid transport was reduced after one week of the HF diet, which persisted throughout the study and was not inherited, whereas intracellular metabolism was decreased after six weeks and inherited. An increased inherited gene expression of fructose transport was observed after one and six weeks, potentially leading to increased de novo lipogenesis. Conclusion: An isocaloric dietary increase of fat induced a tightly orchestrated, partially inherited network of genes responsible for fatty acid and carbohydrate transport and metabolism in human s.c. WAT.

Loos, Ruth J F/0000-0002-8532-5087; Huibregtse, Brooke M./0000-0003-0977-7249; Kandler, Christian/0000-0002-9175-235X; Hjelmborg, Jacob/0000-0001-9630-9149; mangino, massimo/0000-0002-2167-7470; Siribaddana, Sisira/0000-0001-5821-2557; Plomin, Robert/0000-0002-0756-3629; Latvala, Antti/0000-0001-5695-117X; Kaprio, Jaakko/0000-0002-3716-2455; Willemsen, Gonneke/0000-0003-3755-0236; Tan, Qihua/0000-0003-3194-0030; Pahlen, Shandell/0000-0003-0753-4155; Pedersen, Nancy/0000-0001-8057-3543; Haworth, Claire/0000-0002-8608-289X; Nistico, Lorenza/0000-0003-1805-6240; Skytthe, Axel/0000-0002-8629-4913; van Beijsterveldt, Toos/0000-0002-6617-4201; Rebato, Esther/0000-0003-1221-8501; Li, Lintao/0000-0002-0604-9660; Bartels, Meike/0000-0002-9667-7555; Silventoinen, Karri/0000-0003-1759-3079; Cunha Oliveira, Vinicius/0000-0002-8658-3774; Sund, Reijo/0000-0002-6268-8117; Sodemann, Morten/0000-0001-8992-2500; Rasmussen, Finn/0000-0001-7915-7809; Harden, Kathryn/0000-0002-1557-6737; Medda, Emanuela/0000-0003-4837-4549; Kyvik, Kirsten Ohm/0000-0003-2981-0245; Colodro Conde, Lucia/0000-0002-9004-364X WOS: 000517442200060 PubMed: 31364586 The COllaborative project of Development of Anthropometrical measures in Twins (CODATwins) project is a large international collaborative effort to analyze individual-level phenotype data from twins in multiple cohorts from different environments. The main objective is to study factors that modify genetic and environmental variation of height, body mass index (BMI, kg/m(2)) and size at birth, and additionally to address other research questions such as long-term consequences of birth size. The project started in 2013 and is open to all twin projects in the world having height and weight measures on twins with information on zygosity. Thus far, 54 twin projects from 24 countries have provided individual-level data. The CODATwins database includes 489,981 twin individuals (228,635 complete twin pairs). Since many twin cohorts have collected longitudinal data, there is a total of 1,049,785 height and weight observations. For many cohorts, we also have information on birth weight and length, own smoking behavior and own or parental education. We found that the heritability estimates of height and BMI systematically changed from infancy to old age. Remarkably, only minor differences in the heritability estimates were found across cultural-geographic regions, measurement time and birth cohort for height and BMI. In addition to genetic epidemiological studies, we looked at associations of height and BMI with education, birth weight and smoking status. Within-family analyses examined differences within same-sex and opposite-sex dizygotic twins in birth size and later development. The CODATwins project demonstrates the feasibility and value of international collaboration to address gene-by-exposure interactions that require large sample sizes and address the effects of different exposures across time, geographical regions and socioeconomic status. Academy of FinlandAcademy of Finland [266592, 100499, 205585, 118555, 141054, 265240, 263278, 264146]; Osaka University's International Joint Research Promotion Program; Centre of Research Excellence Grant from the National Health and Medical Research CouncilNational Health and Medical Research Council of Australia [1079102]; National Institutes of HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [R01 HD068435, R01 MH062375, 1R01ESO15150-01, R21 AG039572]; National Medical Research Council Research Fellowship; California Tobacco-Related Disease Research ProgramUniversity of California System [7RT-0134H, 8RT-0107H, 6RT-0354H]; National Institute on AgingUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute on Aging (NIA) [1RO1-AG13662-01A2]; Swedish Research Council through the Swedish Initiative for Research on Microdata in the Social And Medical Sciences (SIMSAM) [340-2013-5867]; Swedish Heart-Lung FoundationSwedish Heart-Lung Foundation; Swedish Asthma and Allergy Association's Research Foundation; Special Fund for Health Scientific Research in the Public Welfare, China [201502006]; NIDAUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute on Drug Abuse (NIDA) [DA011015, HD10333]; National Program for Research Infrastructure 2007 from the Danish Agency for Science, Technology and Innovation; Research Council for Health and Disease; Velux Foundation; US National Institute of HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [P01 AG08761]; Fund of Scientific Research, FlandersFWO; ENGAGE - European Network for Genetic and Genomic Epidemiology, FP7-HEALTH-F4-2007 [201413]; National Institute of Alcohol Abuse and AlcoholismUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute on Alcohol Abuse & Alcoholism (NIAAA) [AA-12502, AA-00145, AA-09203]; Academy of Finland Center of Excellence in Complex Disease GeneticsAcademy of Finland [213506, 129680]; Cancer Research UKCancer Research UK [C1418/A7974]; W T Grant Foundation; University of London Central Research fund; Medical Research CouncilMedical Research Council UK (MRC) [G81/343, G120/635]; Economic and Social Research CouncilEconomic & Social Research Council (ESRC) [RES-000-22-2206]; Institute of Social Psychiatry [06/07-11]; Leverhulme Research FellowshipLeverhulme Trust [RF/2/RFG/2008/0145]; Goldsmiths, University of London; UK Medical Research CouncilMedical Research Council UK (MRC) [MR/M021475/1, G0901245]; National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London; NIHUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [R01AG053217, RC2 HL103416]; National Natural Science Foundation of ChinaNational Natural Science Foundation of China [81125007]; Global Research Network Program of the National Research Foundation [NRF 2011-220-E00006]; European Research Council (ERC)European Research Council (ERC) [240994]; Michigan State University; National Institute of Mental Health (NIMH)United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Mental Health (NIMH) [R01-MH081813, R01-MH0820-54, R01-MH092377-02, R21-MH070542-01, R03-MH63851-01, 1R01-MH118848-01]; Eunice Kennedy Shriver National Institute for Child Health and Human Development (NICHD) [R01-HD066040]; MSU Foundation [11-SPG-2518]; Fundacion Seneca, Regional Agency for Science and Technology, Murcia, Spain [08633/PHCS/08, 15302/PHCS/10, 19479/PI/14]; Ministry of Science and Innovation, SpainSpanish Government [PSI2009-11560, PSI2014-56680-R]; MagW/ZonMW [904-61-090, 985-10-002, 912-10-020, 904-61-193, 480-04-004, 463-06-001, 451-04-034, 400-05-717, Addiction-31160008, Middelgroot-911-09-032, Spinozapremie 56-464-14192]; European Research CouncilEuropean Research Council (ERC) [ERC-230374]; JSPS KAKENHI JP [23593419, 24792601, 26671010, 24590695, 26293128, 16K15385, 16K15978, 16K15989, 16H03261]; Australian National Health and Medical Research CouncilNational Health and Medical Research Council of Australia [437015, 607358]; Bonnie Babes Foundation [BBF20704]; Financial Markets Foundation for Children [032-2007]; Victorian Government; Portuguese agency for research (The Foundation for Science and Technology [FCT]) [POCI/DES/56834/2004]; Wellcome TrustWellcome Trust; Medical Research CouncilMedical Research Council UK (MRC); European UnionEuropean Union (EU); National Institute for Health Research (NIHR)National Institute for Health Research (NIHR); King's College London; Fonds Quebecois de la Recherche sur la Societe et la CultureFQRNT; Fonds de la Recherche en Sante du QuebecFonds de la Recherche en Sante du Quebec; Social Science and Humanities Research Council of Canada; National Health Research Development Program; Canadian Institutes for Health ResearchCanadian Institutes of Health Research (CIHR); Sainte-Justine Hospital's Research Center; Canada Research Chair ProgramCanada Research Chairs; National Research Foundation of KoreaNational Research Foundation of Korea [NRF-371-2011-1 B00047]; Swedish Research CouncilSwedish Research Council [2017-00641]; UK Biotechnology and Biological Sciences Research CouncilBiotechnology and Biological Sciences Research Council (BBSRC) [31/D19086]; MRCMedical Research Council UK (MRC) [MR/M021475/1]; Krkkale University [2009/43]; TUBITAKTurkiye Bilimsel ve Teknolojik Arastirma Kurumu (TUBITAK) [114C117]; National Institute of Mental HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Mental Health (NIMH) [R01 MH58354]; National Institute of HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [NIA R01 AG018384, R01 AG018386, R01 AG022381, R01 AG022982]; VA San Diego Center of Excellence for Stress and Mental Health; Cooperative Studies Program of the Office of Research & Development of the United States Department of Veterans Affairs; Japan Society for the Promotion of ScienceMinistry of Education, Culture, Sports, Science and Technology, Japan (MEXT)Japan Society for the Promotion of Science [15H05105]; Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust; Stockholm County Council (ALF-projects)Stockholm County Council; Twins, a nonprofit Association for Scientific Research in Multiple Births (Belgium); [5T32DA017637]; [5T32AG052371] This study was conducted within the CODATwins project (Academy of Finland #266592). K Silventoinen is supported by Osaka University's International Joint Research Promotion Program. This research was facilitated through access to Twins Research Australia, a national resource supported by a Centre of Research Excellence Grant (ID: 1079102), from the National Health and Medical Research Council. The Boston University Twin Project is funded by grants (#R01 HD068435 #R01 MH062375) from the National Institutes of Health to K. Saudino. Paulo Ferreira is funded by a National Medical Research Council Research Fellowship. California Twin Program was supported by The California Tobacco-Related Disease Research Program (7RT-0134H, 8RT-0107H, 6RT-0354H) and the National Institutes of Health (1R01ESO15150-01).; The Carolina African American Twin Study of Aging (CAATSA) was funded by a grant from the National Institute on Aging (grant 1RO1-AG13662-01A2) to K. E. Whitfield. The CATSS-Study is supported by the Swedish Research Council through the Swedish Initiative for Research on Microdata in the Social And Medical Sciences (SIMSAM) framework grant no 340-2013-5867, grants provided by the Stockholm County Council (ALF-projects), the Swedish Heart-Lung Foundation and the Swedish Asthma and Allergy Association's Research Foundation.; Chinese National Twin Registry is funded by Special Fund for Health Scientific Research in the Public Welfare (Project No: 201502006), China. Colorado Twin Registry is funded by NIDA-funded center grant DA011015, & Longitudinal Twin Study HD10333; Author Huibregtse is supported by 5T32DA017637 and 5T32AG052371. Danish Twin Registry is supported by the National Program for Research Infrastructure 2007 from the Danish Agency for Science, Technology and Innovation, The Research Council for Health and Disease, the Velux Foundation and the US National Institute of Health (P01 AG08761). Since its origin, the East Flanders Prospective Survey has been partly supported by grants from the Fund of Scientific Research, Flanders and Twins, a nonprofit Association for Scientific Research in Multiple Births (Belgium). Data collection and analyses in Finnish twin cohorts have been supported by ENGAGE - European Network for Genetic and Genomic Epidemiology, FP7-HEALTH-F4-2007, grant agreement number 201413, National Institute of Alcohol Abuse and Alcoholism (grants AA-12502, AA-00145 and AA-09203 to R J Rose, the Academy of Finland Center of Excellence in Complex Disease Genetics (grant numbers: 213506, 129680), and the Academy of Finland (grants 100499, 205585, 118555, 141054, 265240, 263278 and 264146 to J Kaprio). Gemini was supported by a grant from Cancer Research UK (C1418/A7974). Waves 1-3 of Genesis 12-19 were funded by the W T Grant Foundation, the University of London Central Research fund and a Medical Research Council Training Fellowship (G81/343) and Career Development Award (G120/635) to Thalia C. Eley. Wave 4 was supported by grants from the Economic and Social Research Council (RES-000-22-2206) and the Institute of Social Psychiatry (06/07-11) to Alice M. Gregory, who was also supported at that time by a Leverhulme Research Fellowship (RF/2/RFG/2008/0145). Wave 5 was supported by funding to Alice M. Gregory from Goldsmiths, University of London. T. C. Eley is partly funded by a program grant from the UK Medical Research Council (MR/M021475/1).; This study presents independent research [partly] funded by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. The Minnesota Twin Registry (MTR) acknowledges support from NIH grant R01AG053217. Guangzhou Twin Eye Study is supported by National Natural Science Foundation of China (grant #81125007). Anthropometric measurements of the Hungarian twins were supported by Medexpert Ltd., Budapest, Hungary. Korean Twin-Family Register was supported by the Global Research Network Program of the National Research Foundation (NRF 2011-220-E00006). Longitudinal Israeli Study of Twins was funded by the Starting Grant no. 240994 from the European Research Council (ERC) to Ariel Knafo. The Michigan State University Twin Registry has been supported by Michigan State University, as well as grants R01-MH081813, R01-MH0820-54, R01-MH092377-02, R21-MH070542-01, R03-MH63851-01 and 1R01-MH118848-01 from the National Institute of Mental Health (NIMH), R01-HD066040 from the Eunice Kennedy Shriver National Institute for Child Health and Human Development (NICHD) and 11-SPG-2518 from the MSU Foundation. The content of this paper is solely the responsibility of the authors and does not necessarily represent the official views of the NIMH, the NICHD or the National Institutes of Health. The Murcia Twin Registry is supported by Fundacion Seneca, Regional Agency for Science and Technology, Murcia, Spain (08633/PHCS/08, 15302/PHCS/10 & 19479/PI/14) and Ministry of Science and Innovation, Spain (PSI2009-11560 & PSI2014-56680-R). The NAS-NRC Twin Registry acknowledges financial support from the National Institutes of Health grant number R21 AG039572. Netherlands Twin Register acknowledges the Netherlands Organization for Scientific Research (NWO) and MagW/ZonMW grants 904-61-090, 985-10-002, 912-10-020, 904-61-193,480-04-004, 463-06-001, 451-04-034, 400-05-717, Addiction-31160008, Middelgroot-911-09-032, Spinozapremie 56-464-14192; VU University's Institute for Health and Care Research (EMGO+); the European Research Council (ERC-230374), the Avera Institute, Sioux Falls, South Dakota (USA). Osaka University Aged Twin Registry is supported by grants from JSPS KAKENHI JP (23593419, 24792601, 26671010, 24590695, 26293128, 16K15385, 16K15978, 16K15989, 16H03261). PETS was supported by grants from the Australian National Health and Medical Research Council (grant numbers 437015 and 607358 to JC, and RS), the Bonnie Babes Foundation (grant number BBF20704 to JMC), the Financial Markets Foundation for Children (grant no. 032-2007 to JMC), and by the Victorian Government's Operational Infrastructure Support Program.; Madeira data comes from the following project: Genetic and environmental influences on physical activity, fitness and health: the Madeira family study Project reference: POCI/DES/56834/2004 Founded by the Portuguese agency for research (The Foundation for Science and Technology [FCT]). TwinsUK receives funding from the Wellcome Trust, Medical Research Council and European Union.; TwinsUK and M. Mangino are supported by the National Institute for Health Research (NIHR)-funded BioResource, Clinical Research Facility and Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust in partnership with King's College London. The Quebec Newborn Twin Study acknowledges financial support from the Fonds Quebecois de la Recherche sur la Societe et la Culture, the Fonds de la Recherche en Sante du Quebec, the Social Science and Humanities Research Council of Canada, the National Health Research Development Program, the Canadian Institutes for Health Research, Sainte-Justine Hospital's Research Center, and the Canada Research Chair Program (Michel Boivin). South Korea Twin Registry is supported by National Research Foundation of Korea (NRF-371-2011-1 B00047). We acknowledge The Swedish Twin Registry for access to data. The Swedish Twin Registry is managed by Karolinska Institutet and receives funding through the Swedish Research Council under the grant no. 2017-00641.; The Twins Early Development Study (TEDS) is supported by a program grant (G0901245) from the UK Medical Research Council and the work on obesity in TEDS is supported in part by a grant from the UK Biotechnology and Biological Sciences Research Council (31/D19086). Currently TEDS is supported by MRC grant 'MR/M021475/1'. The Texas Twin Project is currently funded by grant R01HD083613 from the National Institutes of Health. S. Y. oncel and F. Aliev are supported by Krkkale University Research Grant: KKU, 2009/43 and TUBITAK grant 114C117. The University of Southern California Twin Study is funded by a grant from the National Institute of Mental Health (R01 MH58354). Washington State Twin Registry (formerly the University of Washington Twin Registry) was supported in part by grant NIH RC2 HL103416 (D. Buchwald, PI). Vietnam Era Twin Study of Aging was supported by National Institute of Health grants NIA R01 AG018384, R01 AG018386, R01 AG022381 and R01 AG022982, and, in part, with resources of the VA San Diego Center of Excellence for Stress and Mental Health. The Cooperative Studies Program of the Office of Research & Development of the United States Department of Veterans Affairs has provided financial support for the development and maintenance of the Vietnam Era Twin (VET) Registry. The content of this paper is solely the responsibility of the authors and does not necessarily represent the official views of the NIA/NIH, or the VA. The West Japan Twins and Higher Order Multiple Births Registry was supported by Grant-in-Aid for Scientific Research (B) (grant number 15H05105) from the Japan Society for the Promotion of Science.

Pregnancy-induced hypertension is a severe pregnancy complication, increasing risk of long-term cardiovascular disease in mothers and offspring. We hypothesized that maternal blood pressure in pregnancy associated with offspring blood pressure; that the associations were sex-specific; and that maternal circulating placental angiogenic markers (PlGF [placental growth factor] and sFlt-1 [soluble fms-like tyrosine kinase-1]) mediated this relationship. We analyzed data from 2434 women and 2217 children from the Odense Child Cohort, a prospective Danish cohort study. Offspring blood pressure trajectory from 4 months to 5 years was highly associated to maternal first, second, and third trimester blood pressure, and mean blood pressure in pregnancy, independent of maternal and offspring covariates. There were offspring sex-specific associations: Girls from mothers in the highest quartile of first and third trimester blood pressure had significantly higher systolic blood pressure at 5 years than the rest of the cohort (mean difference±SEM: 1.81±0.59 and 2.11±0.59 mm Hg, respectively, all P P

Obesity is associated with increased levels of soluble Dipeptidyl Peptidase-4 (DPP-4) in serum leading to adipose tissue inflammation and insulin resistance. Animal studies, however, have shown that a high fat diet acutely decreases serum DDP-4 levels. This study investigated the response of serum DDP-4 to a sudden switch from a healthy isocaloric low fat diet to an isocaloric high fat diet (HFD) in healthy human twins. 35 monzyogotic and 11 dizygotic healthy pairs of twins (women and men, age 18 - 70) were investigated for 12 weeks. An isocaloric diet rich in carbohydrates (55% carbohydrates, 30% fat, 15% protein, LF) was applied for 6 weeks, followed by an isocaloric diet rich in saturated fat (40% carbohydrates, 45% fat, 15% protein, HF) for another 6 weeks. Body weight (BW) and serum concentrations of DPP-4, tumor necrosis factor α (TNFα) and insulin were analyzed after the LF period, after one week (HF1w) and at the end (HF6w) of the HF period. Total body fat and lean mass were determined by DEXA-Scan at LF and HF6w. BW was constant over the time of intervention. Serum DPP-4 protein was decreased by 15% at HF1w and by 18% at HF6w, respectively, compared to LF (both P Disclosure M. Kruse: None. A. Ost: None. S. Hornemann: None. D. Hoffmann: None. T. Frahnow: None. A. Busjahn: None. A.F. Pfeiffer: None. Funding German Federal Ministry of Education and Research (0315424)

The angiogenic factors sFlt-1 (soluble fms-like tyrosine kinase) and PlGF (Placental Growth Factor) play a key role in the pathophysiology, prediction and diagnosis of preeclampsia-associated pregnancy disorders. However, the correlation between maternal serum levels and the placental weight, especially in hypertensive pregnancy disorders is still unclear.Retrospectively, we analyzed data from a real-world cohort of patients with preeclampsia (PE), intrauterine growth restriction (IUGR), PE + IUGR and controls giving birth within 14 days from inclusion. Herein, correlational analyses were calculated between placental weight, maternal serum levels of sFlt-1, PlGF and the respective sFlt-1/PlGF-ratios.This study included n = 328 patients (n = 134 with PE, n = 40 with IUGR and n = 25 showed PE + IUGR) and n = 129 controls. The gestational age-adjusted placental weight was significantly decreased in patients with PE ± IUGR, but not in PE alone, when comparing to controls. Correlation between PlGF and the placental weight was significantly positive and increasing with severity of disease (controls 0.134, p = 0.131, PE 0.419, p 0.01, IUGR 0.517, p 0.01, PE + IUGR r = 0.723, p 0.01). Furthermore, an inverse correlation between the sFlt-1/PlGF-ratio and the placental weight was found. The sFlt-1/PlGF-ratio per gram placental weight was highest in patients with PE + IUGR and lowest in controls (0.6 (IQR 0.4-1.8) vs. 0.05 (IQR 0.02-0.15)).A correlation between the serum levels of sFlt-1 and PlGF and the placental weight is present in PE-associated pregnancy disorders. This mirrors the model of an angiogenic continuum in the placenta where the serum sFlt-1 to PlGF ratio increases with severity of the disease.

To date no biomarker has been identified bringing together perfect sensitivity and specificity to discriminate between inflammation and infections. Since the 1930s new markers of tissue damage and endothelial damage have been identified but which are incapable of identifying infections in every clinical setting to enable initiation of early antibiotic treatment. In this review the most important classical biomarkers and upcoming new PCR-based approaches are addressed. These markers are highlighted with respect to special clinical settings and to control the success of antibiotic treatment. The issue of discrimination between inflammation and infection is not yet solved. Based on one single biomarker it is impossible to decide whether infection is the reason for the patient's worsening condition but the combination of biomarkers or the integration of new biomarkers may be a meaningful supplement. The measurement of different biomarkers of infection or inflammation is part of the routine in critical care and will be essential in the future.Die Identifikation eines Biomarkers, der idealerweise eine perfekte Sensitivität und Spezifität mitbringt, um eine Inflammation von einer Infektion zu unterscheiden, ist bis heute nicht gelungen. Seit mehr als 80 Jahren werden immer neue Marker der Gewebs- und Endothelschädigung identifiziert, die jedoch nicht in jeder klinischen Situation eine Infektion sicher identifizieren können und damit eine frühe Initiierung einer Antibiotikatherapie ermöglichen. In dieser Übersicht werden die wichtigsten, etablierten „klassischen“ Biomarker ebenso wie neue, molekularbiologische Ansätze angesprochen und im Hinblick auf spezielle klinische Situationen und die Steuerung einer Antibiotikatherapie beleuchtet. Das Problem der Differenzierung zwischen Infektion und Inflammation ist bis heute nicht gelöst. Anhand eines singulären Biomarkers ist die Entscheidung unsicher zu treffen, ob eine Infektion ursächlich für eine sich aggravierende Situation ist, aber unter bestimmten klinischen Bedingungen kann die Kombination von Biomarkern oder die Einbindung neuer Biomarker eine sinnvolle Ergänzung darstellen. Die Bestimmung verschiedener Biomarker einer Infektion oder Inflammation ist Teil der intensivmedizinischen Routine und wird auch in Zukunft unverzichtbar sein.

Loos, Ruth J F/0000-0002-8532-5087; Sund, Reijo/0000-0002-6268-8117; Busjahn, Andreas/0000-0001-9650-6919; Tan, Qihua/0000-0003-3194-0030; Aliev, Fazil/0000-0001-8357-4699; Kaprio, Jaakko/0000-0002-3716-2455; Magnusson, Patrik/0000-0002-7315-7899; Tan, Qihua/0000-0003-3194-0030; ONCEL, Sevgi YURT/0000-0002-0990-292X; Ordonana, Juan R./0000-0001-7779-6017; Colodro-Conde, Lucia/0000-0002-9004-364X; Huibregtse, Brooke M./0000-0003-0977-7249; ROMERA, JUAN FRANCISCO SANCHEZ/0000-0002-5405-6216; Rebato, Esther/0000-0003-1221-8501; Pedersen, Nancy/0000-0001-8057-3543; Latvala, Antti/0000-0001-5695-117X; Silventoinen, Karri/0000-0003-1759-3079; Rasmussen, Finn/0000-0001-7915-7809; Piirtola, Maarit/0000-0001-7270-6676 WOS: 000438457400025 PubMed: 30001359 Background Smokers tend to weigh less than never smokers, while successful quitting leads to an increase in body weight. Because smokers and non-smokers may differ in genetic and environmental family background, we analysed data from twin pairs in which the co-twins differed by their smoking behaviour to evaluate if the association between smoking and body mass index (BMI) remains after controlling for family background. Methods and findings The international CODATwins database includes information on smoking and BMI measured between 1960 and 2012 from 156,593 twin individuals 18-69 years of age. Individual-based data (230,378 measurements) and data of smoking discordant twin pairs (altogether 30,014 pairwise measurements, 36% from monozygotic [MZ] pairs) were analysed with linear fixed-effects regression models by 10-year periods. In MZ pairs, the smoking co-twin had, on average, 0.57 kg/m(2) lower BMI in men (95% confidence interval (CI): 0.49, 0.70) and 0.65 kg/m(2) lower BMI in women (95% CI: 0.52, 0.79) than the never smoking co-twin. Former smokers had 0.70 kg/m(2) higher BMI among men (95% CI: 0.63, 0.78) and 0.62 kg/m(2) higher BMI among women (95% CI: 0.51, 0.73) than their currently smoking MZ cotwins. Little difference in BMI was observed when comparing former smoking co-twins with their never smoking MZ co-twins (0.13 kg/m(2), 95% CI 0.04, 0.23 among men; -0.04 kg/m(2), 95% CI -0.16, 0.09 among women). The associations were similar within dizygotic pairs and when analysing twins as individuals. The observed series of cross-sectional associations were independent of sex, age, and measurement decade. Conclusions Smoking is associated with lower BMI and smoking cessation with higher BMI. However, the net effect of smoking and subsequent cessation on weight development appears to be minimal, i.e. never more than an average of 0.7 kg/m(2). Academy of FinlandAcademy of Finland [266592, 100499, 205585, 118555, 141054, 265240, 263278, 264146]; Fund of Scientific Research, Flanders and Twins, a non-profit Association for Scientific Research in Multiple Births (Belgium); ENGAGE - European Network for Genetic and Genomic Epidemiology [FP7- HEALTH-F4-2007, 201413]; National Institute of Alcohol Abuse and AlcoholismUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute on Alcohol Abuse & Alcoholism (NIAAA) [AA-12502, AA-00145, AA-09203]; Academy of Finland Center of Excellence in Complex Disease GeneticsAcademy of Finland [213506, 129680]; Sigrid Juselius FoundationSigrid Juselius Foundation; Osaka University's International Joint Research Promotion Program; Medexpert Ltd., Budapest, Hungary; European Union's Seventh Framework Programmes ENGAGE ConsortiumEuropean Union (EU) [HEALTH-F4- 2007-201413]; BioSHaRE EU [HEALTH-F4-2010-261433]; Fundacion Seneca, Regional Agency for Science and Technology, Murcia, Spain [08633/PHCS/08, 15302/PHCS/10, 19479/PI/14]; Ministry of Science and Innovation, SpainSpanish Government [PSI2009-11560, PSI2014-56680-R]; Centre of Research Excellence grant from the National Health and Medical Research CouncilNational Health and Medical Research Council of Australia [1079102]; Australian National Health and Medical Research CouncilNational Health and Medical Research Council of Australia; Australian Research CouncilAustralian Research Council; Australian National Health and Medical Research Council fellowshipNational Health and Medical Research Council of Australia [SRFB-1103623]; National Institutes of Health grantUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [R21 AG039572]; National Institute of HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [NIA R01 AG018384, R01 AG018386, R01 AG022381, R01 AG022982]; Cooperative Studies Program of the Office of Research & Development of the United States Department of Veterans Affairs; NIDAUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute on Drug Abuse (NIDA) [DA011015]; Longitudinal Twin Study [HD10333]; JSPS KAKENHI JP [23593419, 24792601, 26671010, 24590695, 26293128, 16K15385, 16K15978, 16K15989, 16H03261]; Global Research Network Program of the National Research Foundation [NRF 2011-220- E00006]; Kirikkale University Research Grant: KKUKirikkale University [2009/43]; TUBITAKTurkiye Bilimsel ve Teknolojik Arastirma Kurumu (TUBITAK) [114C117]; [5T32DA017637]; [5T32AG052371] This study was conducted within the CODATwins project (Academy of Finland grant #266592 to KS). Since its origin, the East Flanders Prospective Survey has been partly supported by grants from the Fund of Scientific Research, Flanders and Twins, a non-profit Association for Scientific Research in Multiple Births (Belgium). Data collection and analyses in Finnish twin cohorts have been supported by ENGAGE - European Network for Genetic and Genomic Epidemiology, FP7- HEALTH-F4-2007 (grant agreement number 201413), National Institute of Alcohol Abuse and Alcoholism (grants AA-12502, AA-00145, and AA-09203 to RJ Rose), the Academy of Finland Center of Excellence in Complex Disease Genetics (grant numbers: 213506, 129680), and the Academy of Finland (grants 100499, 205585, 118555, 141054, 265240, 263278 and 264146 to JK). JK also acknowledges support from the Sigrid Juselius Foundation. KS is supported by Osaka University's International Joint Research Promotion Program. Anthropometric measurements of the Hungarian twins were supported by Medexpert Ltd., Budapest, Hungary. Data collection and research stemming from the Norwegian Twin Registry is supported, in part, from the European Union's Seventh Framework Programmes ENGAGE Consortium (grant agreement HEALTH-F4- 2007-201413), and BioSHaRE EU (grant agreement HEALTH-F4-2010-261433). The Murcia Twin Registry is supported by Fundacion Seneca, Regional Agency for Science and Technology, Murcia, Spain (08633/PHCS/08, 15302/PHCS/10 & 19479/PI/14) and Ministry of Science and Innovation, Spain (PSI2009-11560 & PSI2014-56680-R). The Australian Twin Registry is supported by a Centre of Research Excellence grant (ID 1079102) from the National Health and Medical Research Council administered by the University of Melbourne. The QIMR twin study acknowledges grants from the Australian National Health and Medical Research Council and the Australian Research Council. SM is supported by an Australian National Health and Medical Research Council fellowship (SRFB-1103623). The NAS-NRC Twin Registry acknowledges financial support from the National Institutes of Health grant number R21 AG039572. The Vietnam Era Twin Study of Aging was supported by National Institute of Health grants NIA R01 AG018384, R01 AG018386, R01 AG022381, and R01 AG022982, and, in part, with resources from the VA San Diego Center of Excellence for Stress and Mental Health. The Cooperative Studies Program of the Office of Research & Development of the United States Department of Veterans Affairs has provided financial support for the development and maintenance of the Vietnam Era Twin (VET) Registry. The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the NIA/NIH, or the VA. The Colorado Twin Registry is funded by NIDA-funded center grant DA011015 and Longitudinal Twin Study HD10333; BH was supported by 5T32DA017637 and 5T32AG052371. The Osaka University Aged Twin Registry is supported by grants from JSPS KAKENHI JP (23593419, 24792601, 26671010, 24590695, 26293128, 16K15385, 16K15978, 16K15989, 16H03261). The Korean Twin-Family Register was supported by the Global Research Network Program of the National Research Foundation (NRF 2011-220- E00006). SO and FA are supported by Kirikkale University Research Grant: KKU, 2009/43 and TUBITAK grant 114C117.; None of the funders including HealthTwiSt GmbH and Pfizer Inc played a role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript and only provided financial support in the form of authors' salaries, excluding HealthTwiSt GmbH and Pfizer Inc, and/or research materials. The funder HealthTwiSt GmbH did not provide support in the form of salaries for authors (AB). HealthTwiSt GmbH collects data on twin samples and makes these available to academic researchers for a service fee to cover the costs (technical staff salaries and material costs). The funder (Pfizer Inc) did provide support in the form of consultation fees for authors (JK and TK) outside of the submitted work.

Kaprio, Jaakko/0000-0002-3716-2455; Knafo-Noam, Ariel/0000-0003-0613-1960; de Freitas, Duarte Luis/0000-0001-6642-3370; Haworth, Claire/0000-0002-8608-289X; Siribaddana, Sisira/0000-0001-5821-2557; Kyvik, Kirsten O/0000-0003-2981-0245; Aliev, Fazil/0000-0001-8357-4699; Craig, Jeffrey M/0000-0003-3979-7849; Ordonana, Juan R./0000-0001-7779-6017; Sund, Reijo/0000-0002-6268-8117; Bartels, Meike/0000-0002-9667-7555; Kandler, Christian/0000-0002-9175-235X; Fagnani, Corrado/0000-0001-5771-7772; Huibregtse, Brooke M./0000-0003-0977-7249; Montgomery, Grant W/0000-0002-4140-8139; Colodro-Conde, Lucia/0000-0002-9004-364X; Loos, Ruth J F/0000-0002-8532-5087; Busjahn, Andreas/0000-0001-9650-6919; ONCEL, Sevgi YURT/0000-0002-0990-292X; Christensen, Kaare/0000-0002-5429-5292; Martin, Nicholas/0000-0003-4069-8020; Tan, Qihua/0000-0003-3194-0030; ROMERA, JUAN FRANCISCO SANCHEZ/0000-0002-5405-6216; D'Ippolito, Cristina/0000-0001-7902-9380; Skytthe, Axel E/0000-0002-8629-4913; Tan, Qihua/0000-0003-3194-0030; Heikkila, Kauko/0000-0002-9256-8028; Duncan, Glen/0000-0001-6909-1869; Jelenkovic, Aline/0000-0002-6191-8371; Magnusson, Patrik/0000-0002-7315-7899; mangino, massimo/0000-0002-2167-7470; Medland, Sarah E/0000-0003-1382-380X; Saffery, Richard/0000-0002-9510-4181; Plomin, Robert/0000-0002-0756-3629; Harden, Kathryn/0000-0002-1557-6737; Hotopf, Matthew/0000-0002-3980-4466; McAdams, Tom/0000-0002-6825-3499; Aaltonen, Sari/0000-0002-2873-4263; Kremen, William/0000-0002-8629-5609; Pahlen, Shandell/0000-0003-0753-4155; Llewellyn, Clare/0000-0002-0066-2827; Franz, Carol/0000-0002-8987-1755; Derom, Catherine/0000-0001-5574-796X; Willemsen, Gonneke/0000-0003-3755-0236; Rasmussen, Finn/0000-0001-7915-7809; Rebato, Esther/0000-0003-1221-8501; lee, kayoung/0000-0002-2816-554X; Sodemann, Morten/0000-0001-8992-2500; Gatz, Margaret/0000-0002-1071-9970; Boivin, Michel/0000-0001-8621-9844; Silventoinen, Karri/0000-0003-1759-3079 WOS: 000358874400002 PubMed: 26014041 For over 100 years, the genetics of human anthropometric traits has attracted scientific interest. In particular, height and body mass index (BMI, calculated as kg/m(2)) have been under intensive genetic research. However, it is still largely unknown whether and how heritability estimates vary between human populations. Opportunities to address this question have increased recently because of the establishment of many new twin cohorts and the increasing accumulation of data in established twin cohorts. We started a new research project to analyze systematically (1) the variation of heritability estimates of height, BMI and their trajectories over the life course between birth cohorts, ethnicities and countries, and (2) to study the effects of birth-related factors, education and smoking on these anthropometric traits and whether these effects vary between twin cohorts. We identified 67 twin projects, including both monozygotic (MZ) and dizygotic (DZ) twins, using various sources. We asked for individual level data on height and weight including repeated measurements, birth related traits, background variables, education and smoking. By the end of 2014, 48 projects participated. Together, we have 893,458 height and weight measures (52% females) from 434,723 twin individuals, including 201,192 complete twin pairs (40% monozygotic, 40% same-sex dizygotic and 20% opposite-sex dizygotic) representing 22 countries. This project demonstrates that large-scale international twin studies are feasible and can promote the use of existing data for novel research purposes. National Institute of Mental HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Mental Health (NIMH) [R01 MH58354]; National Institute on AgingUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute on Aging (NIA) [1RO1-AG13662-01A2]; National Institutes of HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [R21 AG039572]; WT Grant Foundation; University of London Central Research fund; Medical Research CouncilMedical Research Council UK (MRC) [G81/343, G120/635]; Economic and Social Research CouncilEconomic & Social Research Council (ESRC) [RES-000-22-2206]; Institute of Social Psychiatry [06/07-11]; Leverhulme Research FellowshipLeverhulme Trust [RF/2/RFG/2008/0145]; Goldsmiths; University of London; National Research Foundation of KoreaNational Research Foundation of Korea [NRF-371-2011-1B00047]; Danish Agency for Science, Technology and Innovation; Research Council for Health and Disease; Velux Foundation; US National Institute of HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [P01 AG08761]; Fund of Scientific Research, FlandersFWO; Twins, a non-profit Association for Scientific Research in Multiple Births (Belgium); Global Research Network Program of the National Research Foundation [NRF 2011-220-E00006]; NIDAUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute on Drug Abuse (NIDA) [DA011015]; Longitudinal Twin Study [HD10333]; National Institute of Health grantsUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [NIA R01 AG018384, R01 AG018386, R01 AG022381, R01 AG022982]; Cooperative Studies Program of the Office of Research AMP; Development of the United States Department of Veterans Affairs; Centre of Research Excellence from the National Health and Medical Research CouncilNational Health and Medical Research Council of Australia [1079102]; Michigan State University from the National Institute of Mental Health (NIMH) [R01-MH081813, R01-MH0820-54, R01-MH092377-02, R21-MH070542-01, R03-MH63851-01]; Eunice Kennedy Shriver National Institute for Child Health and Human Development (NICHD) [R01-HD066040]; MSU Foundation [11-SPG-2518]; California Tobacco-Related Disease Research ProgramUniversity of California System [7RT-0134H, 8RT-0107H, 6RT-0354H]; The National Institutes of HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [1R01ESO15150-01]; National Natural Science Foundation of ChinaNational Natural Science Foundation of China [81125007]; Australian National Health and Medical Research CouncilNational Health and Medical Research Council of Australia [437015, 607358]; Bonnie Babes Foundation [BBF20704]; Financial Markets Foundation for Children [032-2007]; Victorian Government's Operational Infrastructure Support Program; ENGAGE-European Network for Genetic and Genomic Epidemiology [201413]; National Institute of Alcohol Abuse and AlcoholismUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute on Alcohol Abuse & Alcoholism (NIAAA) [AA-12502, AA-00145, AA-09203]; Academy of Finland Center of Excellence in Complex Disease GeneticsAcademy of Finland [213506, 129680]; Academy of FinlandAcademy of Finland [100499, 205585, 118555, 141054, 265240, 263278, 264146]; Osaka University's International Joint Research Promotion Program; Kirikkale University Research Grant: KKUKirikkale University; TUBITAKTurkiye Bilimsel ve Teknolojik Arastirma Kurumu (TUBITAK) [114C117]; European Research Council (ERC)European Research Council (ERC) [240994]; European Union's Seventh Framework Programmes ENGAGE ConsortiumEuropean Union (EU) [HEALTH-F4-2007-201413]; BioSHaRE EU [HEALTH-F4-2010-261433]; Seneca FoundationFundacion Seneca; Regional Agency for Science and Technology, Murcia, Spain [08633/PHCS/08, 15302/PHCS/10]; Ministry of Science and Innovation, SpainSpanish Government [PSI11560-2009]; UK Medical Research CouncilMedical Research Council UK (MRC) [G0901245]; UK Biotechnology and Biological Sciences Research CouncilBiotechnology and Biological Sciences Research Council (BBSRC) [31/D19086]; Portuguese agency for research (The Foundation for Science and Technology) [POCI/DES/56834/2004]; National Institutes of Health.United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [R01 HD068435, R01 MH062375]; Wellcome TrustWellcome Trust; European Community's Seventh Framework ProgrammeEuropean Union (EU); National Institute for Health Research (NIHR) BioResource Clinical Research Facility and Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust and King's College London; Netherlands Organization for Scientific Research (NWO)Netherlands Organization for Scientific Research (NWO); MagW/ZonMW [904-61-090, 985-10-002, 912-10-020, 904-61-193, 480-04-004, 463-06-001, 451-04-034, 400-05-717, Addiction-31160008, Middelgroot-911-09-032, Spinozapremie 56-464-14192]; VU University's Institute for Health and Care Research (EMGO+); European Research CouncilEuropean Research Council (ERC) [ERC-230374]; Avera Institute, Sioux Falls, South Dakota (USA); Cancer Research UKCancer Research UK [C1418/A7974]; [5T32DA017637-10]; [NIH RC2 HL103416]; Cancer Research UKCancer Research UK [14133]; Medical Research CouncilMedical Research Council UK (MRC) [G0901245, MC_UU_12013/1]; NNF Center for Basic Metabolic ResearchNovo Nordisk Foundation [Metabolic Genetics]; Novo Nordisk FondenNovo NordiskNovo Nordisk Foundation [NNF10CC1016515] This study was conducted within the CODATwins project (Academy of Finland #266592). Support for participating twin projects: the University of Southern California Twin Study is funded by a grant from the National Institute of Mental Health (R01 MH58354). The Carolina African American Twin Study of Aging (CAATSA) was funded by a grant from the National Institute on Aging (grant 1RO1-AG13662-01A2) to K. E. Whitfield. The NAS-NRC Twin Registry acknowledges financial support from the National Institutes of Health grant number R21 AG039572. Waves 1-3 of Genesis 12-19 were funded by the WT Grant Foundation, the University of London Central Research fund and a Medical Research Council Training Fellowship (G81/343) and Career Development Award (G120/635) to Thalia C. Eley. Wave 4 was supported by grants from the Economic and Social Research Council (RES-000-22-2206) and the Institute of Social Psychiatry (06/07-11) to Alice M. Gregory who was also supported at that time by a Leverhulme Research Fellowship (RF/2/RFG/2008/0145). Wave 5 was supported by funding to Alice M. Gregory from Goldsmiths, University of London. Anthropometric measurements of the Hungarian twins were supported by Medexpert Ltd., Budapest, Hungary. South Korea Twin Registry is supported by National Research Foundation of Korea (NRF-371-2011-1B00047). The Danish Twin Registry is supported by the National Program for Research Infrastructure 2007 from the Danish Agency for Science, Technology and Innovation, The Research Council for Health and Disease, the Velux Foundation and the US National Institute of Health (P01 AG08761). Since its origin, the East Flanders Prospective Survey has been partly supported by grants from the Fund of Scientific Research, Flanders and Twins, a non-profit Association for Scientific Research in Multiple Births (Belgium). Korean Twin-Family Register was supported by the Global Research Network Program of the National Research Foundation (NRF 2011-220-E00006). The Colorado Twin Registry is funded by NIDA funded center grant DA011015 and Longitudinal Twin Study HD10333; Author Huibregtse is supported by 5T32DA017637-10. The Vietnam Era Twin Study of Aging was supported by National Institute of Health grants NIA R01 AG018384, R01 AG018386, R01 AG022381, and R01 AG022982, and, in part, with resources of the VA San Diego Center of Excellence for Stress and Mental Health. The Cooperative Studies Program of the Office of Research & Development of the United States Department of Veterans Affairs has provided financial support for the development and maintenance of the Vietnam Era Twin (VET) Registry. The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the NIA/NIH, or the VA. The Australian Twin Registry is supported by a Centre of Research Excellence (grant ID 1079102) from the National Health and Medical Research Council administered by the University of Melbourne. The Michigan State University Twin Registry has been supported by Michigan State University, as well as grants R01-MH081813, R01-MH0820-54, R01-MH092377-02, R21-MH070542-01, R03-MH63851-01 from the National Institute of Mental Health (NIMH), R01-HD066040 from the Eunice Kennedy Shriver National Institute for Child Health and Human Development (NICHD), and 11-SPG-2518 from the MSU Foundation. The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the NIMH, the NICHD, or the National Institutes of Health.; r The California Twin Program was supported by The California Tobacco-Related Disease Research Program (7RT-0134H, 8RT-0107H, 6RT-0354H) and the National Institutes of Health (1R01ESO15150-01). The Guangzhou Twin Eye Study is supported by National Natural Science Foundation of China (grant #81125007). PETS was supported by grants from the Australian National Health and Medical Research Council (grant numbers 437015 and 607358 to JC, and RS), the Bonnie Babes Foundation (grant number BBF20704 to JMC), the Financial Markets Foundation for Children (grant no. 032-2007 to JMC), and by the Victorian Government's Operational Infrastructure Support Program. Data collection and analyses in Finnish twin cohorts have been supported by ENGAGE-European Network for Genetic and Genomic Epidemiology, FP7-HEALTH-F4-2007, grant agreement number 201413, National Institute of Alcohol Abuse and Alcoholism (grants AA-12502, AA-00145, and AA-09203 to R. J. Rose, the Academy of Finland Center of Excellence in Complex Disease Genetics (grant numbers: 213506, 129680), and the Academy of Finland (grants 100499, 205585, 118555, 141054, 265240, 263278 and 264146 to J. Kaprio). K. Silventoinen is supported by Osaka University's International Joint Research Promotion Program. S. Y. Oncel and F. Aliev are supported by Kirikkale University Research Grant: KKU, 2009/43 and TUBITAK grant 114C117. The Longitudinal Israeli Study of Twins was funded by the Starting Grant no. 240994 from the European Research Council (ERC) to Ariel Knafo. Data collection and research stemming from the Norwegian Twin Registry is supported, in part, from the European Union's Seventh Framework Programmes ENGAGE Consortium (grant agreement HEALTH-F4-2007-201413, and BioSHaRE EU (grant agreement HEALTH-F4-2010-261433). The Murcia Twin Registry is supported by the Seneca Foundation, Regional Agency for Science and Technology, Murcia, Spain (08633/PHCS/08 & 15302/PHCS/10) and Ministry of Science and Innovation, Spain (PSI11560-2009). The Twins Early Development Study (TEDS) is supported by a program grant (G0901245) from the UK Medical Research Council and the work on obesity in TEDS is supported in part by a grant from the UK Biotechnology and Biological Sciences Research Council (31/D19086). The Madeira data comes from the following project: genetic and environmental influences on physical activity, fitness, and health: the Madeira family study Project reference: POCI/DES/56834/2004 founded by the Portuguese agency for research (The Foundation for Science and Technology). The Boston University Twin Project is funded by grants (#R01 HD068435 #R01 MH062375) from the National Institutes of Health to K. Saudino. TwinsUK was funded by the Wellcome Trust; European Community's Seventh Framework Programme (FP7/2007-2013). The study also receives support from the National Institute for Health Research (NIHR) BioResource Clinical Research Facility and Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust and King's College London. The University of Washington Twin Registry is supported by the grant NIH RC2 HL103416 (D. Buchwald, PI). The Netherlands Twin Register acknowledges the Netherlands Organization for Scientific Research (NWO) and MagW/ZonMW grants 904-61-090, 985-10-002, 912-10-020, 904-61-193,480-04-004, 463-06-001, 451-04-034, 400-05-717, Addiction-31160008, Middelgroot-911-09-032, Spinozapremie 56-464-14192; VU University's Institute for Health and Care Research (EMGO+); the European Research Council (ERC-230374), the Avera Institute, Sioux Falls, South Dakota (USA).; r Gemini was supported by a grant from Cancer Research UK (C1418/A7974).

Das Lesen von Quelltext ist ein essentieller Teil des Programmverstehens. Während die Analyse von Blickbewegungen seit Jahrzehnten wertvolle Einblicke in das Verstehen von natürlichsprachlichem Text liefert, ist sie beim Programmverstehen relativ neu und es ergeben sich eine Reihe methodischer Probleme. Diese Arbeit evaluiert und adaptiert methodische Ansätze, so werden u.a. eine spezifische Ereignisdetektion und ein neues Korrekturverfahren für räumliche Fehler entwickelt. Die Eignung der beschriebenen Methodik wird mit zwei exemplarischen Forschungsfragen demonstriert. Zunächst wird analysiert, ob natürlichsprachlicher Text und Quelltext unterschiedlich gelesen werden. Die zweite Frage betrifft die Unterschiede zwischen Anfänger:innen und Expert:innen. Für ein umfassendes Bild wird ein breites Spektrum etablierter als auch speziell entwickelter Analysemaße eingesetzt, z.B. Sequenzalignment zur Beschreibung von Leseansätzen. Bereits Anfänger:innen lesen Quelltext teilweise anders als natürlichsprachlichen Text, bei Expert:innen sind die Unterschiede noch ausgeprägter. Bei natürlichsprachlichem Text werden mehr Bereiche betrachtet als bei Programmen. Anfänger:innen lesen Quelltext zum Teil anders als Expert:innen, so befassen sich letztere viel früher mit der main-Methode. Blickbewegungen liefern reichhaltige Informationen über das Quelltextlesen. Die entwickelte Methodik lässt sich auf viele Fragen im Bereich der Softwaretechnik und der Programmierausbildung anwenden., Code reading is a fundamental part of program comprehension. While studying eye movements has provided valuable insights into natural-language text comprehension for decades, its application in program comprehension is fairly recent and brings about many methodological challenges. This work evaluates and adapts existing methodological approaches, resulting in a customized event detection and a novel correction for spatial error. The suitability of the proposed methodology is demonstrated with two exemplary research questions. First, it is analyzed whether natural-language text and source code are read differently. The second question concerns differences in how novices and experts read programs. To obtain a comprehensive picture of code reading, a wide range of established as well as specifically devised measures is used for analysis, e.g. sequence alignment is adapted into an instrument for examining reading approaches. In some regards novices already read source code differently than natural-language text, for experts the differences are even more pronounced. Participants look at a greater proportion of natural-language text than of source code. Novices partly exhibit a different code reading behavior than experts, e.g. the latter attend to the main-method much sooner. Eye movements provide manifold information to deepen the understanding of code reading. The developed methodology can be applied to many questions in software engineering and programming education.

An autoimmune reaction directed against the cardiac b1-adrenergic receptor (beta1-ADR) leading to the generation of autoantibodies (AA) against this G-coupled receptor has been described in patients with heart failure (HF). Agonist-like beta1-ADR-AA are associated with morbidity in HF patients and even predict mortality. Standardised and valid diagnostic tools to detect beta 1-ADR-AA in clinical routine are lacking. We used a novel ELISA approach to investigate beta 1-ADR-AA in a cohort of 574 HF patients of the CIBIS-ELD trial with follow up. The CIBIS-ELD trial compared the titration of bisoprolol and carvedilol to recommended target doses in regard to BB tolerability in patients aged 65 years and older. Patient with left ventricular (LV) ejection fraction (EF) less than 50% or LV diameter end diastolic (DED) more than 55 cm showed significantly higher levels of beta1-ADR-AA. Although not yet fully validated, this ELISA allowed for a negative correlation of beta1-ADR-AA with the EF at baseline and at the follow up, beta1-ADR-AA further correlated positively with basal heart rate at follow up 12 weeks later. beta1-ADR-AA levels thus determined significantly increased under titration with beta-blockers (pless than 0.01). Changes in beta1-ADR-AA between F-Up and baseline were significantly higher in patients who used beta blockers (p=0.016) before study inclusion. The type of beta-blocker titrated in this study did not affect log beta1-ADR-AA levels at baseline (p=0.132), follow-up (p=0.058), nor the change (p=0.426). beta1-ADR-AA levels were estimated using a novel, commercially available ELISA. Although not yet fully validated, this ELISA allowed for pathophysiological insights: beta1-ADR-AA levels thus determined significantly increased under titration with beta-blockers (pless than 0.01), irrespective of type of BB. Higher levels of beta1-ADR-AA at baseline are associated with higher heart rates, lower ejection fraction and enlarged left ventricles. The relevance of the beta1-ADR-AA biomarker should be further evaluated.

Background and purpose External counterpulsation improves cerebral perfusion velocity in acute stroke and may stimulate collateral artery growth. However, whether (non-acute) at-risk patients with high-grade carotid artery disease may benefit from counterpulsation needs to be validated. Methods Twenty-eight patients (71 ± 6.5 years, five women) with asymptomatic unilateral chronic severe internal carotid artery stenosis (>70%) or occlusion were randomized to receive 20 min active counterpulsation followed by sham treatment or vice versa. Cerebral blood flow velocity (CBFV) (measured bilaterally by transcranial middle cerebral artery Doppler), tissue oxygenation index (TOI) (measured over the bilateral prefrontal cortex by near-infrared spectroscopy) and cerebral hemodynamic parameters, such as relative pulse slope index (RPSI), were monitored. Results Ipsilateral mean CBFV (ΔVmean +3.5 ± 1.2 cm/s) and tissue oxygenation (ΔTOI +2.86 ± 0.8) increased significantly during active counterpulsation compared to baseline, whilst the sham had little effect (ΔVmean +1.13 ± 1.1 cm/s; ΔTOI +1.25 ± 0.65). On contralateral sides, neither counterpulsation nor sham control had any effect on either parameter. During counterpulsation, early dynamic changes in ΔRPSI of the ipsilateral CBFV signal predicted improved tissue oxygenation during counterpulsation (odds ratio 1.179, 95% confidence interval 1.01-1.51), whilst baseline cerebrovascular reactivity to hypercapnia failed to show an association. Conclusions In patients with high-grade carotid disease, ipsilateral cerebral oxygenation and blood flow velocity are increased by counterpulsation. This is a necessary condition for the stimulation of regenerative collateral artery growth and thus a therapeutic concept for the prevention of cerebral ischaemia. This study provides a rationale for further clinical investigations on the long-term effects of counterpulsation on cerebral hemodynamics and collateral growth.

Loos, Ruth J F/0000-0002-8532-5087; Huibregtse, Brooke M./0000-0003-0977-7249; Busjahn, Andreas/0000-0001-9650-6919; Skytthe, Axel E/0000-0002-8629-4913; Heikkila, Kauko/0000-0002-9256-8028; Haworth, Claire/0000-0002-8608-289X; Hjelmborg, Jacob/0000-0001-9630-9149; Sund, Reijo/0000-0002-6268-8117; Aliev, Fazil/0000-0001-8357-4699; Fagnani, Corrado/0000-0001-5771-7772; Kaprio, Jaakko/0000-0002-3716-2455; Knafo-Noam, Ariel/0000-0003-0613-1960; Montgomery, Grant W/0000-0002-4140-8139; Moller, Soren/0000-0003-0858-4269; ONCEL, Sevgi YURT/0000-0002-0990-292X; Duncan, Glen/0000-0001-6909-1869; Medland, Sarah E/0000-0003-1382-380X; Kandler, Christian/0000-0002-9175-235X; Christensen, Kaare/0000-0002-5429-5292; Magnusson, Patrik/0000-0002-7315-7899; mangino, massimo/0000-0002-2167-7470; Bartels, Meike/0000-0002-9667-7555; de Freitas, Duarte Luis/0000-0001-6642-3370; Harden, Kathryn/0000-0002-1557-6737; Derom, Catherine/0000-0001-5574-796X; Plomin, Robert/0000-0002-0756-3629; Silventoinen, Karri/0000-0003-1759-3079; Rasmussen, Finn/0000-0001-7915-7809; Boivin, Michel/0000-0001-8621-9844; Saffery, Richard/0000-0002-9510-4181; Pahlen, Shandell/0000-0003-0753-4155; van Beijsterveldt, Toos/0000-0002-6617-4201; Rebato, Esther/0000-0003-1221-8501; Pedersen, Nancy/0000-0001-8057-3543; Aaltonen, Sari/0000-0002-2873-4263; Llewellyn, Clare/0000-0002-0066-2827; Kyvik, Kirsten Ohm/0000-0003-2981-0245; Sodemann, Morten/0000-0001-8992-2500; Willemsen, Gonneke/0000-0003-3755-0236; D'Ippolito, Cristina/0000-0001-7902-9380; McAdams, Tom/0000-0002-6825-3499 WOS: 000378317900001 PubMed: 27333805 Height variation is known to be determined by both genetic and environmental factors, but a systematic description of how their influences differ by sex, age and global regions is lacking. We conducted an individual-based pooled analysis of 45 twin cohorts from 20 countries, including 180,520 paired measurements at ages 1-19 years. The proportion of height variation explained by shared environmental factors was greatest in early childhood, but these effects remained present until early adulthood. Accordingly, the relative genetic contribution increased with age and was greatest in adolescence (up to 0.83 in boys and 0.76 in girls). Comparing geographic-cultural regions (Europe, North-America and Australia, and East-Asia), genetic variance was greatest in North-America and Australia and lowest in East-Asia, but the relative proportion of genetic variation was roughly similar across these regions. Our findings provide further insights into height variation during childhood and adolescence in populations representing different ethnicities and exposed to different environments. Academy of FinlandAcademy of Finland [266592, 100499, 205585, 118555, 141054, 265240, 263278, 264146]; National Institutes of HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [R01 HD068435, R01 MH062375, 1R01ESO15150-01, AA023322, HD081437, R21 AG039572]; California Tobacco-Related Disease Research ProgramUniversity of California System [7RT-0134H, 8RT-0107H, 6RT-0354H]; Special Fund for Health Scientific Research in the Public Welfare, China [201502006]; NIDAUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute on Drug Abuse (NIDA) [DA011015, HD10333]; National Program for Research Infrastructure from the Danish Agency for Science, Technology and Innovation; Research Council for Health and Disease; Velux Foundation; US National Institute of HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [P01 AG08761]; Fund of Scientific Research, Flanders and Twins; NGAGE-European Network for Genetic and Genomic Epidemiology [FP7-HEALTH-F4-2007, 201413]; National Institute of Alcohol Abuse and AlcoholismUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute on Alcohol Abuse & Alcoholism (NIAAA) [AA-12502, AA-00145, AA-09203]; Academy of Finland Center of Excellence in Complex Disease GeneticsAcademy of Finland [213506, 129680]; Osaka University's International Joint Research Promotion Program; Cancer Research UKCancer Research UK [C1418/A7974]; WT Grant Foundation; University of London Central Research fund; Medical Research Council Training FellowshipMedical Research Council UK (MRC) [G81/343, G120/635]; Economic and Social Research CouncilEconomic & Social Research Council (ESRC) [RES-000-22-2206]; Institute of Social Psychiatry [06/07-11]; Leverhulme Research FellowshipLeverhulme Trust [RF/2/RFG/2008/0145]; Goldsmiths, University of London; National Natural Science Foundation of ChinaNational Natural Science Foundation of China [81125007]; Medexpert Ltd., Budapest, Hungary; European Research Council (ERC)European Research Council (ERC) [240994]; Michigan State University; National Institute of Mental Health (NIMH)United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Mental Health (NIMH) [R01-MH081813, R01-MH0820-54, R01-MH092377-02, R21-MH070542-01, R03-MH63851-01]; Eunice Kennedy Shriver National Institute for Child Health and Human Development (NICHD) [R01-HD066040]; MSU Foundation [11-SPG-2518]; Netherlands Organization for Scientific Research (NWO)Netherlands Organization for Scientific Research (NWO); MagW/ZonMW [904-61-090, 985-10-002, 912-10-020, 904-61-193, 480-04-004, 463-06-001, 451-04-034, 400-05-717, Addiction-31160008, Middelgroot-911-09-032, Spinozapremie 56-464-14192]; VU University's Institute for Health and Care Research (EMGO+); European Research CouncilEuropean Research Council (ERC) [ERC-230374]; Avera Institute, Sioux Falls, South Dakota (USA); Australian National Health and Medical Research CouncilNational Health and Medical Research Council of Australia [437015, 607358]; Bonnie Babes Foundation [BBF20704]; Financial Markets Foundation for Children [032-2007]; Victorian Government's Operational Infrastructure Support Program; Portuguese agency for research (The Foundation for Science and Technology [FCT]) [POCI/DES/56834/2004]; Fonds Quebecois de la Recherche sur la Societe et la CultureFQRNT; Fonds de la Recherche en Sante du QuebecFonds de la Recherche en Sante du Quebec; Social Science and Humanities Research Council of Canada; National Health Research Development Program; Canadian Institutes for Health ResearchCanadian Institutes of Health Research (CIHR); Sainte-Justine Hospital's Research Center; Canada Research Chair ProgramCanada Research Chairs; National Research Foundation of KoreaNational Research Foundation of Korea [NRF-371-2011-1 B00047]; UK Medical Research CouncilMedical Research Council UK (MRC) [G0901245]; UK Biotechnology and Biological Sciences Research CouncilBiotechnology and Biological Sciences Research Council (BBSRC) [31/D19086]; Kirikkale University Research Grant: KKUKirikkale University [2009/43]; TUBITAKTurkiye Bilimsel ve Teknolojik Arastirma Kurumu (TUBITAK) [114C117]; Wellcome TrustWellcome Trust; European Community's Seventh Framework Programme (FP7)European Union (EU); National Institute for Health Research (NIHR) BioResource Clinical Research Facility and Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust and King's College London; National Institute of Mental HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Mental Health (NIMH) [R01 MH58354]; NIHUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [RC2 HL103416]; Japan Society for the Promotion of ScienceMinistry of Education, Culture, Sports, Science and Technology, Japan (MEXT)Japan Society for the Promotion of Science [15H05105]; [5T32DA017637-11]; Medical Research CouncilMedical Research Council UK (MRC) [G19/2, MR/M021475/1, G120/635, G0500079, G0901245]; NNF Center for Basic Metabolic ResearchNovo Nordisk Foundation [Metabolic Genetics]; Novo Nordisk FondenNovo NordiskNovo Nordisk Foundation [NNF10CC1016515] This study was conducted within the CODATwins project (Academy of Finland #266592). Support for participating twin projects: The Boston University Twin Project is funded by grants (#R01 HD068435 #R01 MH062375) from the National Institutes of Health to K. Saudino. California Twin Program was supported by The California Tobacco-Related Disease Research Program (7RT-0134H, 8RT-0107H, 6RT-0354H) and the National Institutes of Health (1R01ESO15150-01). Chinese National Twin Registry is funded by Special Fund for Health Scientific Research in the Public Welfare (Project No: 201502006), China. Colorado Twin Registry is funded by NIDA funded center grant DA011015, & Longitudinal Twin Study HD10333; Author Huibregtse is supported by to 5T32DA017637-11. Danish Twin Registry is supported by the National Program for Research Infrastructure 2007 from the Danish Agency for Science, Technology and Innovation, The Research Council for Health and Disease, the Velux Foundation and the US National Institute of Health (P01 AG08761). Since its origin the East Flanders Prospective Survey has been partly supported by grants from the Fund of Scientific Research, Flanders and Twins, a non-profit Association for Scientific Research in Multiple Births (Belgium). Data collection and analyses in Finnish twin cohorts have been supported by ENGAGE-European Network for Genetic and Genomic Epidemiology, FP7-HEALTH-F4-2007, grant agreement number 201413, National Institute of Alcohol Abuse and Alcoholism (grants AA-12502, AA-00145, and AA-09203 to RJ Rose, the Academy of Finland Center of Excellence in Complex Disease Genetics (grant numbers: 213506, 129680), and the Academy of Finland (grants 100499, 205585, 118555, 141054, 265240, 263278 and 264146 to J. Kaprio). K. Silventoinen is supported by Osaka University's International Joint Research Promotion Program. Gemini was supported by a grant from Cancer Research UK (C1418/A7974). Waves 1-3 of Genesis 12-19 were funded by the WT Grant Foundation, the University of London Central Research fund and a Medical Research Council Training Fellowship (G81/343) and Career Development Award (G120/635) to Thalia C. Eley. Wave 4 was supported by grants from the Economic and Social Research Council (RES-000-22-2206) and the Institute of Social Psychiatry (06/07-11) to Alice M. Gregory who was also supported at that time by a Leverhulme Research Fellowship (RF/2/RFG/2008/0145). Wave 5 was supported by funding to Alice M. Gregory from Goldsmiths, University of London. Guangzhou Twin Eye Study is supported by National Natural Science Foundation of China (grant #81125007). Anthropometric measurements of the Hungarian twins were supported by Medexpert Ltd., Budapest, Hungary. Longitudinal Israeli Study of Twins was funded by the Starting Grant no. 240994 from the European Research Council (ERC) to Ariel Knafo. The Michigan State University Twin Registry has been supported by Michigan State University, as well as grants R01-MH081813, R01-MH0820-54, R01-MH092377-02, R21-MH070542-01, R03-MH63851-01 from the National Institute of Mental Health (NIMH), R01-HD066040 from the Eunice Kennedy Shriver National Institute for Child Health and Human Development (NICHD), and 11-SPG-2518 from the MSU Foundation. The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the NIMH, the NICHD, or the National Institutes of Health. The NAS-NRC Twin Registry acknowledges financial support from the National Institutes of Health grant number R21 AG039572.; Netherlands Twin Register acknowledges the Netherlands Organization for Scientific Research (NWO) and MagW/ZonMW grants 904-61-090, 985-10-002, 912-10-020, 904-61-193,480-04-004, 463-06-001, 451-04-034, 400-05-717, Addiction-31160008, Middelgroot-911-09-032, Spinozapremie 56-464-14192; VU University's Institute for Health and Care Research (EMGO+); the European Research Council (ERC-230374), the Avera Institute, Sioux Falls, South Dakota (USA). PETS was supported by grants from the Australian National Health and Medical Research Council (grant numbers 437015 and 607358 to J. C. and R.S.), the Bonnie Babes Foundation (grant number BBF20704 to J. M. C.), the Financial Markets Foundation for Children (grant no. 032-2007 to J. M. C.), and by the Victorian Government's Operational Infrastructure Support Program. Madeira data comes from the following project: Genetic and environmental influences on physical activity, fitness and health: the Madeira family study Project reference: POCI/DES/56834/2004 Founded by the Portuguese agency for research (The Foundation for Science and Technology [FCT]). The Quebec Newborn Twin Study acknowledges financial support from the Fonds Quebecois de la Recherche sur la Societe et la Culture, the Fonds de la Recherche en Sante du Quebec, the Social Science and Humanities Research Council of Canada, the National Health Research Development Program, the Canadian Institutes for Health Research, Sainte-Justine Hospital's Research Center, and the Canada Research Chair Program (Michel Boivin). South Korea Twin Registry is supported by National Research Foundation of Korea (NRF-371-2011-1 B00047). The Texas Twin Project is currently funded by grants AA023322 and HD081437 from the National Institutes of Health. The Twins Early Development Study (TEDS) is supported by a program grant (G0901245) from the UK Medical Research Council and the work on obesity in TEDS is supported in part by a grant from the UK Biotechnology and Biological Sciences Research Council (31/D19086). S.Y. Oncel and F. Aliev are supported by Kirikkale University Research Grant: KKU, 2009/43 and TUBITAK grant 114C117. TwinsUK was funded by the Wellcome Trust; European Community's Seventh Framework Programme (FP7/2007-2013). The study also receives support from the National Institute for Health Research (NIHR) BioResource Clinical Research Facility and Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust and King's College London. The University of Southern California Twin Study is funded by a grant from the National Institute of Mental Health (R01 MH58354). Washington State Twin Registry (formerly the University of Washington Twin Registry) was supported in part by grant NIH RC2 HL103416 (D. Buchwald, PI). The West Japan Twins and Higher Order Multiple Births Registry was supported by Grant-in-Aid for Scientific Research (B) (grant number 15H05105) from the Japan Society for the Promotion of Science.