The trans-ancestral genomic architecture of glycemic traits

Glycemic traits are used to diagnose and monitor type 2 diabetes and cardiometabolic health. To date, most genetic studies of glycemic traits have focused on individuals of European ancestry. Here we aggregated genome-wide association studies comprising up to 281,416 individuals without diabetes (30% non-European ancestry) for whom fasting glucose, 2-h glucose after an oral glucose challenge, glycated hemoglobin and fasting insulin data were available. Trans-ancestry and single-ancestry meta-analyses identified 242 loci (99 novel; P < 5 x 10(-8)), 80% of which had no significant evidence of between-ancestry heterogeneity. Analyses restricted to individuals of European ancestry with equivalent sample size would have led to 24 fewer new loci. Compared with single-ancestry analyses, equivalent-sized trans-ancestry fine-mapping reduced the number of estimated variants in 99% credible sets by a median of 37.5%. Genomic-feature, gene-expression and gene-set analyses revealed distinct biological signatures for each trait, highlighting different underlying biological pathways. Our results increase our understanding of diabetes pathophysiology by using trans-ancestry studies for improved power and resolution.A trans-ancestry meta-analysis of GWAS of glycemic traits in up to 281,416 individuals identifies 99 novel loci, of which one quarter was found due to the multi-ancestry approach, which also improves fine-mapping of credible variant sets.Diabetes mellitus: pathophysiological changes and therap

Global, regional, and national age-sex-specific mortality and life expectancy, 1950–2017: a systematic analysis for the Global Burden of Disease Study 2017

BACKGROUND: Assessments of age-specific mortality and life expectancy have been done by the UN Population Division, Department of Economics and Social Affairs (UNPOP), the United States Census Bureau, WHO, and as part of previous iterations of the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD). Previous iterations of the GBD used population estimates from UNPOP, which were not derived in a way that was internally consistent with the estimates of the numbers of deaths in the GBD. The present iteration of the GBD, GBD 2017, improves on previous assessments and provides timely estimates of the mortality experience of populations globally. METHODS: The GBD uses all available data to produce estimates of mortality rates between 1950 and 2017 for 23 age groups, both sexes, and 918 locations, including 195 countries and territories and subnational locations for 16 countries. Data used include vital registration systems, sample registration systems, household surveys (complete birth histories, summary birth histories, sibling histories), censuses (summary birth histories, household deaths), and Demographic Surveillance Sites. In total, this analysis used 8259 data sources. Estimates of the probability of death between birth and the age of 5 years and between ages 15 and 60 years are generated and then input into a model life table system to produce complete life tables for all locations and years. Fatal discontinuities and mortality due to HIV/AIDS are analysed separately and then incorporated into the estimation. We analyse the relationship between age-specific mortality and development status using the Socio-demographic Index, a composite measure based on fertility under the age of 25 years, education, and income. There are four main methodological improvements in GBD 2017 compared with GBD 2016: 622 additional data sources have been incorporated; new estimates of population, generated by the GBD study, are used; statistical methods used in different components of the analysis have been further standardised and improved; and the analysis has been extended backwards in time by two decades to start in 1950. FINDINGS: Globally, 18·7% (95% uncertainty interval 18·4–19·0) of deaths were registered in 1950 and that proportion has been steadily increasing since, with 58·8% (58·2–59·3) of all deaths being registered in 2015. At the global level, between 1950 and 2017, life expectancy increased from 48·1 years (46·5–49·6) to 70·5 years (70·1–70·8) for men and from 52·9 years (51·7–54·0) to 75·6 years (75·3–75·9) for women. Despite this overall progress, there remains substantial variation in life expectancy at birth in 2017, which ranges from 49·1 years (46·5–51·7) for men in the Central African Republic to 87·6 years (86·9–88·1) among women in Singapore. The greatest progress across age groups was for children younger than 5 years; under-5 mortality dropped from 216·0 deaths (196·3–238·1) per 1000 livebirths in 1950 to 38·9 deaths (35·6–42·83) per 1000 livebirths in 2017, with huge reductions across countries. Nevertheless, there were still 5·4 million (5·2–5·6) deaths among children younger than 5 years in the world in 2017. Progress has been less pronounced and more variable for adults, especially for adult males, who had stagnant or increasing mortality rates in several countries. The gap between male and female life expectancy between 1950 and 2017, while relatively stable at the global level, shows distinctive patterns across super-regions and has consistently been the largest in central Europe, eastern Europe, and central Asia, and smallest in south Asia. Performance was also variable across countries and time in observed mortality rates compared with those expected on the basis of development. INTERPRETATION: This analysis of age-sex-specific mortality shows that there are remarkably complex patterns in population mortality across countries. The findings of this study highlight global successes, such as the large decline in under-5 mortality, which reflects significant local, national, and global commitment and investment over several decades. However, they also bring attention to mortality patterns that are a cause for concern, particularly among adult men and, to a lesser extent, women, whose mortality rates have stagnated in many countries over the time period of this study, and in some cases are increasing

Part mounting revisited

Having been involved with single point diamond turning since the 1960's; I share with others of my age, a unique perspective of the craft. I am amazed at how the fundamentals seem to be forgotten or misplaced, and need to be re emphasized and re learned. Each new precision machine operator not only needs to re learn (many times the hard way), these fundamentals, but seems to inherit all the folklore; good and bad, from his predecessor. Let me explain. I spend some of my time as a consultant to the shops' division at the Los Alamos National Laboratory, at which there are five precision turning machines divided between two buildings. The main shop area houses an old friction way (hydrodynamic) turning Machine. The base of this turning machine is made from the base of an old Moore measuring machine. The air bearing spindle, a Red Head'' was made by the Heald Machine Tool Co. With the addition of an Allen-Bradley Numerical control system, this machine has become a work horse, used primarily to make smooth flat surfaces in the fly-cutting mode. Recently, I became involved in the evaluation and repair of the machine as it no longer produced smooth surfaces. Smooth surfaces are not the point of this narrative, accurate geometry however is

Effect of exercise on the nasal transmucosal potential difference in patients with cystic fibrosis and normal subjects.

BACKGROUND--Normal subjects have a negative nasal transmucosal potential difference (TPD) at rest which becomes more negative with exercise. Patients with cystic fibrosis have a more negative resting nasal TPD than controls. The present study was designed to determine the effects of exercise on the TPD of patients with cystic fibrosis. METHODS--Seven subjects with cystic fibrosis and seven control subjects had their usual TPD measured at rest, and during and after a 12 minute period on an exercise bicycle designed to produce a pulse rate of 80% of their maximum predicted value. RESULTS--The normal subjects developed a more negative nasal TPD during exercise which returned towards normal at the completion of the rest period. The patients with cystic fibrosis had higher resting values which became less negative during exercise. At the end of the exercise period there was no difference between the two groups. At the end of the recovery period the results for the patients with cystic fibrosis had returned to their resting values. CONCLUSIONS--Exercise reduces the abnormally high resting values for nasal TPD in patients with cystic fibrosis. Elucidation of the mechanism for this change may help to produce functional improvement for patients with this disease

Acidentes em postos e sistemas retalhistas de combustíveis: subsídios para a vigilância em saúde ambiental Environmental accidents in gas stations and retailling systems

Os acidentes em postos e sistemas retalhistas resultam de forma imediata em danos graves à vida de pessoas, na contaminação do solo e da água. O objetivo deste trabalho foi discutir a importância da atuação conjunta dos órgãos ambientais e de saúde e subsidiar a estruturação do Sistema Nacional de Vigilância em Saúde Ambiental. A metodologia consistiu no estudo da literatura nacional e internacional; levantamento dos dados existentes em oito órgãos ambientais estaduais brasileiros sobre atendimentos emergenciais e análise de um caso ocorrido no município de Guarulhos, Estado de São Paulo, em janeiro de 2005. Os resultados revelaram que esses acidentes são importante causa de acidentes ambientais e há grande diferença na atuação dos diversos órgãos ambientais. Também demonstra que a estruturação da vigilância em saúde ambiental deve abordar a interface com outras instituições públicas envolvidas.<br>The accidents in gas stations and retailing systems result in grave damages to the life of people and contamination of the soil and water. The objective is to discuss the importance of the joint action of environmental and health organs and to subsidize the structuring of the National System of Surveillance in Environmental Health. The methodology consisted of the studying of the national and international literature; to compile the existent data on eight environmental organs about accidents, and analysis of one case occurred in Guarulhos, State of São Paulo, in January, 2005. The results revealed that these accidents are an important cause of environmental accidents and that there is a great difference in the actions of the diverse environmental organs and demonstrates that the structure of surveillance in environmental health should consider the interface with other public institutions