| 1. |
- Ademuyiwa, Adesoji O., et al.
(author)
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Determinants of morbidity and mortality following emergency abdominal surgery in children in low-income and middle-income countries
- 2016
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In: BMJ Global Health. - : BMJ Publishing Group Ltd. - 2059-7908. ; 1:4
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Journal article (peer-reviewed)abstract
- Background: Child health is a key priority on the global health agenda, yet the provision of essential and emergency surgery in children is patchy in resource-poor regions. This study was aimed to determine the mortality risk for emergency abdominal paediatric surgery in low-income countries globally.Methods: Multicentre, international, prospective, cohort study. Self-selected surgical units performing emergency abdominal surgery submitted prespecified data for consecutive children aged <16 years during a 2-week period between July and December 2014. The United Nation's Human Development Index (HDI) was used to stratify countries. The main outcome measure was 30-day postoperative mortality, analysed by multilevel logistic regression.Results: This study included 1409 patients from 253 centres in 43 countries; 282 children were under 2 years of age. Among them, 265 (18.8%) were from low-HDI, 450 (31.9%) from middle-HDI and 694 (49.3%) from high-HDI countries. The most common operations performed were appendectomy, small bowel resection, pyloromyotomy and correction of intussusception. After adjustment for patient and hospital risk factors, child mortality at 30 days was significantly higher in low-HDI (adjusted OR 7.14 (95% CI 2.52 to 20.23), p<0.001) and middle-HDI (4.42 (1.44 to 13.56), p=0.009) countries compared with high-HDI countries, translating to 40 excess deaths per 1000 procedures performed.Conclusions: Adjusted mortality in children following emergency abdominal surgery may be as high as 7 times greater in low-HDI and middle-HDI countries compared with high-HDI countries. Effective provision of emergency essential surgery should be a key priority for global child health agendas.
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| 2. |
- Locke, Adam E, et al.
(author)
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Genetic studies of body mass index yield new insights for obesity biology.
- 2015
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In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 518:7538, s. 197-401
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Journal article (peer-reviewed)abstract
- Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P < 5 × 10(-8)), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for ∼2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.
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| 3. |
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| 4. |
- Lagou, Vasiliki, et al.
(author)
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Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability
- 2021
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In: Nature Communications. - : Nature Publishing Group. - 2041-1723. ; 12:1
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Journal article (peer-reviewed)abstract
- Differences between sexes contribute to variation in the levels of fasting glucose and insulin. Epidemiological studies established a higher prevalence of impaired fasting glucose in men and impaired glucose tolerance in women, however, the genetic component underlying this phenomenon is not established. We assess sex-dimorphic (73,089/50,404 women and 67,506/47,806 men) and sex-combined (151,188/105,056 individuals) fasting glucose/fasting insulin genetic effects via genome-wide association study meta-analyses in individuals of European descent without diabetes. Here we report sex dimorphism in allelic effects on fasting insulin at IRS1 and ZNF12 loci, the latter showing higher RNA expression in whole blood in women compared to men. We also observe sex-homogeneous effects on fasting glucose at seven novel loci. Fasting insulin in women shows stronger genetic correlations than in men with waist-to-hip ratio and anorexia nervosa. Furthermore, waist-to-hip ratio is causally related to insulin resistance in women, but not in men. These results position dissection of metabolic and glycemic health sex dimorphism as a steppingstone for understanding differences in genetic effects between women and men in related phenotypes.
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| 5. |
- Pennells, Lisa, et al.
(author)
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Equalization of four cardiovascular risk algorithms after systematic recalibration : individual-participant meta-analysis of 86 prospective studies
- 2019
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In: European Heart Journal. - : Oxford University Press (OUP). - 0195-668X .- 1522-9645. ; 40:7, s. 621-
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Journal article (peer-reviewed)abstract
- Aims: There is debate about the optimum algorithm for cardiovascular disease (CVD) risk estimation. We conducted head-to-head comparisons of four algorithms recommended by primary prevention guidelines, before and after ‘recalibration’, a method that adapts risk algorithms to take account of differences in the risk characteristics of the populations being studied.Methods and results: Using individual-participant data on 360 737 participants without CVD at baseline in 86 prospective studies from 22 countries, we compared the Framingham risk score (FRS), Systematic COronary Risk Evaluation (SCORE), pooled cohort equations (PCE), and Reynolds risk score (RRS). We calculated measures of risk discrimination and calibration, and modelled clinical implications of initiating statin therapy in people judged to be at ‘high’ 10 year CVD risk. Original risk algorithms were recalibrated using the risk factor profile and CVD incidence of target populations. The four algorithms had similar risk discrimination. Before recalibration, FRS, SCORE, and PCE over-predicted CVD risk on average by 10%, 52%, and 41%, respectively, whereas RRS under-predicted by 10%. Original versions of algorithms classified 29–39% of individuals aged ≥40 years as high risk. By contrast, recalibration reduced this proportion to 22–24% for every algorithm. We estimated that to prevent one CVD event, it would be necessary to initiate statin therapy in 44–51 such individuals using original algorithms, in contrast to 37–39 individuals with recalibrated algorithms.Conclusion: Before recalibration, the clinical performance of four widely used CVD risk algorithms varied substantially. By contrast, simple recalibration nearly equalized their performance and improved modelled targeting of preventive action to clinical need.
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| 6. |
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| 7. |
- Álvarez-Ruiz, Rodrigo, et al.
(author)
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Postflood Monitoring in a Subtropical Estuary and Benchmarking with PFASs Allows Measurement of Chemical Persistence on the Scale of Months
- 2021
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In: Environmental Science and Technology. - : American Chemical Society (ACS). - 0013-936X .- 1520-5851. ; 55:21, s. 14607-14616
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Journal article (peer-reviewed)abstract
- Measurements of chemical persistence in natural environments can provide insight into behavior not easily replicated in laboratory studies. However, it is difficult to find environmental situations suitable for such measurements, particularly for substances with half-lives exceeding several weeks. The objective of this study was to demonstrate that a strategic postflood monitoring campaign can be used to quantify transformation half-lives on the scale of months in a real aquatic system. Water samples were collected in the upper Brisbane River estuary on 36 occasions over 37 weeks and analyzed for 127 pharmaceuticals and personal care products (PPCPs), pesticides, and perfluoroalkyl substances (PFASs). High quality time trend data were obtained for 41 substances. For many of these, data on the input of a wastewater treatment plant to the upper estuary were also obtained. A mass balance model of the estuary stretch was formulated and parametrized using PFASs as persistent benchmarking chemicals. Transformation half-life estimates were obtained for 10 PPCPs and 7 pesticides ranging from 18 to 260 days. Furthermore, insight was obtained into dominant transformation processes as well as the magnitude of chemical inputs to the estuary and their sources. The approach developed shows that under certain conditions, estuaries can be used to quantify the persistence of organic contaminants with half-lives of the order of several months.
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| 8. |
- Bentham, James, et al.
(author)
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A century of trends in adult human height
- 2016
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In: eLIFE. - 2050-084X. ; 5
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Journal article (peer-reviewed)abstract
- Being taller is associated with enhanced longevity, and higher education and earnings. We reanalysed 1472 population-based studies, with measurement of height on more than 18.6 million participants to estimate mean height for people born between 1896 and 1996 in 200 countries. The largest gain in adult height over the past century has occurred in South Korean women and Iranian men, who became 20.2 cm (95% credible interval 17.522.7) and 16.5 cm (13.319.7) taller, respectively. In contrast, there was little change in adult height in some sub-Saharan African countries and in South Asia over the century of analysis. The tallest people over these 100 years are men born in the Netherlands in the last quarter of 20th century, whose average heights surpassed 182.5 cm, and the shortest were women born in Guatemala in 1896 (140.3 cm; 135.8144.8). The height differential between the tallest and shortest populations was 19-20 cm a century ago, and has remained the same for women and increased for men a century later despite substantial changes in the ranking of countries.
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| 9. |
- Bentham, James, et al.
(author)
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A century of trends in adult human height
- 2016
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In: eLIFE. - : eLife Sciences Publications Ltd. - 2050-084X. ; 5
-
Journal article (peer-reviewed)abstract
- Being taller is associated with enhanced longevity, and higher education and earnings. We reanalysed 1472 population-based studies, with measurement of height on more than 18.6 million participants to estimate mean height for people born between 1896 and 1996 in 200 countries. The largest gain in adult height over the past century has occurred in South Korean women and Iranian men, who became 20.2 cm (95% credible interval 17.5–22.7) and 16.5 cm (13.3– 19.7) taller, respectively. In contrast, there was little change in adult height in some sub-Saharan African countries and in South Asia over the century of analysis. The tallest people over these 100 years are men born in the Netherlands in the last quarter of 20th century, whose average heights surpassed 182.5 cm, and the shortest were women born in Guatemala in 1896 (140.3 cm; 135.8– 144.8). The height differential between the tallest and shortest populations was 19-20 cm a century ago, and has remained the same for women and increased for men a century later despite substantial changes in the ranking of countries.
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| 10. |
- Chen, Yiqin, et al.
(author)
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Monthly variation in faeces : blood concentration ratio of persistent organic pollutants over the first year of life
- 2016
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In: Environmental Research. - : Elsevier BV. - 0013-9351 .- 1096-0953. ; 147, s. 259-268
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Journal article (peer-reviewed)abstract
- Previous studies have found that the concentrations of a range of persistent organic pollutants (POPs) in faeces is linearly proportional to the POP concentrations in blood of human adults irrespective of age and gender. In order to investigate the correlation between POP concentrations in faeces and blood in infants, the monthly variation of POP concentrations in faeces over the first year of life of one infant was investigated in this study and compared to modelled blood concentrations. Faecal samples were collected from one male infant daily. The samples were pooled by month and analysed for three selected POPs (2,2',4,4',5,5'-Hexachlorobiphenyl (PCB153), p,p'-dichlorodiphenyldichloroethylene (p,p'-DDE) and 2,2',4,4'-tetrabromodiphenyl ether (BDE47)). The POP concentrations in faecal samples increased for the first four months by a factor of 2.9, 4.9 and 1.4 for PCB153, BDE47, and p,p'-DDE, respectively. The faecal concentrations of all POPs decreased rapidly following the introduction of formula and solid food to the diet and subsequent weaning of the infant. Further, a one-compartment model was developed to estimate the daily POP concentrations in the blood of the infant. The POP concentrations in blood were predicted to vary much less over the first year than those observed in faeces. The faeces:blood concentration ratio of selected POPs (K-fb) differed significantly (P < 0.0001) between the period before and after weaning, and observed changes in K-fb are far greater than the uncertainty in the estimated K-fb. A more stable K-fb after weaning indicates the possibility of applying the stable K-fb values for non-invasive assessment of internal exposure in infants after weaning. The intra-individual variation in K-fb in infants is worthy of further investigation.
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| 11. |
- Chen, Yiqin, et al.
(author)
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Persistent organic pollutants in matched breast milk and infant faeces samples
- 2015
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In: Chemosphere. - : Elsevier BV. - 0045-6535 .- 1879-1298. ; 118, s. 309-314
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Journal article (peer-reviewed)abstract
- Assessing blood concentration of persistent organic pollutants (POPs) in infants is difficult due to the ethical and practical difficulties in obtaining sufficient quantities of blood. To determine whether measuring POPs in faeces might reflect blood concentration during infancy, we measured the concentrations of a range of POPs (i.e. polychlorinated biphenyls (PCBs), polybrominated diphenyl ethers (PBDEs) and organochlorine pesticides (OCPs)) in a pilot study using matched breast milk and infant faecal samples obtained from ten mother-child pairs. All infants were breast fed, with 8 of them also receiving solid food at the time of faecal sampling. In this small dataset faecal concentrations (range 0.01-41 ng g(-1) lipid) are strongly associated with milk concentrations (range 0.02-230 ng g(-1) lipid). Associations with other factors generally could not be detected in this dataset, with the exception of a small effect of age or growth. Different sources (external or internal) of exposure appeared to directly influence faecal concentrations of different chemicals based on different inter-individual variability in the faeces-to-milk concentration ratio R-fm. Overall, the matrix of faeces as an external measure of internal exposure in infants looks promising for some chemicals and is worth assessing further in larger datasets.
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| 12. |
- Clift, Roland, et al.
(author)
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The Challenges of Applying Planetary Boundaries as a Basis for Strategic Decision-Making in Companies with Global Supply Chains
- 2017
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In: Sustainability. - : MDPI AG. - 2071-1050. ; 9:2
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Journal article (peer-reviewed)abstract
- The Planetary Boundaries (PB) framework represents a significant advance in specifying the ecological constraints on human development. However, to enable decision-makers in business and public policy to respect these constraints in strategic planning, the PB framework needs to be developed to generate practical tools. With this objective in mind, we analyse the recent literature and highlight three major scientific and technical challenges in operationalizing the PB approach in decision-making: first, identification of thresholds or boundaries with associated metrics for different geographical scales; second, the need to frame approaches to allocate fair shares in the 'safe operating space' bounded by the PBs across the value chain and; third, the need for international bodies to co-ordinate the implementation of the measures needed to respect the Planetary Boundaries. For the first two of these challenges, we consider how they might be addressed for four PBs: climate change, freshwater use, biosphere integrity and chemical pollution and other novel entities. Four key opportunities are identified: (1) development of a common system of metrics that can be applied consistently at and across different scales; (2) setting 'distance from boundary' measures that can be applied at different scales; (3) development of global, preferably open-source, databases and models; and (4) advancing understanding of the interactions between the different PBs. Addressing the scientific and technical challenges in operationalizing the planetary boundaries needs be complemented with progress in addressing the equity and ethical issues in allocating the safe operating space between companies and sectors.
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| 13. |
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| 14. |
- Fazey, Ioan, et al.
(author)
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Transforming knowledge systems for life on Earth : Visions of future systems and how to get there
- 2020
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In: Energy Research & Social Science. - : Elsevier. - 2214-6296 .- 2214-6326. ; 70
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Journal article (peer-reviewed)abstract
- Formalised knowledge systems, including universities and research institutes, are important for contemporary societies. They are, however, also arguably failing humanity when their impact is measured against the level of progress being made in stimulating the societal changes needed to address challenges like climate change. In this research we used a novel futures-oriented and participatory approach that asked what future envisioned knowledge systems might need to look like and how we might get there. Findings suggest that envisioned future systems will need to be much more collaborative, open, diverse, egalitarian, and able to work with values and systemic issues. They will also need to go beyond producing knowledge about our world to generating wisdom about how to act within it. To get to envisioned systems we will need to rapidly scale methodological innovations, connect innovators, and creatively accelerate learning about working with intractable challenges. We will also need to create new funding schemes, a global knowledge commons, and challenge deeply held assumptions. To genuinely be a creative force in supporting longevity of human and non-human life on our planet, the shift in knowledge systems will probably need to be at the scale of the enlightenment and speed of the scientific and technological revolution accompanying the second World War. This will require bold and strategic action from governments, scientists, civic society and sustained transformational intent.
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| 15. |
- Fenner, Kathrin, et al.
(author)
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Methodological Advances to Study Contaminant Biotransformation : New Prospects for Understanding and Reducing Environmental Persistence?
- 2021
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In: ACS - ES & T Water. - : American Chemical Society (ACS). - 2690-0637. ; 1:7, s. 1541-1554
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Journal article (peer-reviewed)abstract
- Complex microbial communities in environmental systems play a key role in the detoxification of chemical contaminants by transforming them into less active metabolites or by complete mineralization. Biotransformation, i.e., transformation by microbes, is well understood for a number of priority pollutants, but a similar level of understanding is lacking for many emerging contaminants encountered at low concentrations and in complex mixtures across natural and engineered systems. Any advanced approaches aiming to reduce environmental exposure to such contaminants (e.g., novel engineered biological water treatment systems, design of readily degradable chemicals, or improved regulatory assessment strategies to determine contaminant persistence a priori) will depend on understanding the causal links among contaminant removal, the key driving agents of biotransformation at low concentrations (i.e., relevant microbes and their metabolic activities), and how their presence and activity depend on environmental conditions. In this Perspective, we present the current understanding and recent methodological advances that can help to identify such links, even in complex environmental microbiomes and for contaminants present at low concentrations in complex chemical mixtures. We discuss the ensuing insights into contaminant biotransformation across varying environments and conditions and ask how much closer we have come to designing improved approaches to reducing environmental exposure to contaminants.
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| 16. |
- Holmes, Michael V., et al.
(author)
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Mendelian randomization of blood lipids for coronary heart disease
- 2015
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In: European Heart Journal. - : Oxford University Press (OUP). - 1522-9645 .- 0195-668X. ; 36:9, s. 539-539
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Journal article (peer-reviewed)abstract
- Aims To investigate the causal role of high-density lipoprotein cholesterol (HDL-C) and triglycerides in coronary heart disease (CHD) using multiple instrumental variables for Mendelian randomization. Methods and results We developed weighted allele scores based on single nucleotide polymorphisms (SNPs) with established associations with HDL-C, triglycerides, and low-density lipoprotein cholesterol (LDL-C). For each trait, we constructed two scores. The first was unrestricted, including all independent SNPs associated with the lipid trait identified from a priormeta-analysis (threshold P < 2 x 10(-6)); and the second a restricted score, filtered to remove any SNPs also associated with either of the other two lipid traits at P <= 0.01. Mendelian randomization meta-analyses were conducted in 17 studies including 62,199 participants and 12,099 CHD events. Both the unrestricted and restricted allele scores for LDL-C (42 and 19 SNPs, respectively) associated with CHD. For HDL-C, the unrestrictedallele score (48SNPs) was associated with CHD(OR: 0.53; 95% CI: 0.40, 0.70), per 1 mmol/L higher HDL-C, but neither the restricted allele score (19 SNPs; OR: 0.91; 95% CI: 0.42, 1.98) nor the unrestricted HDL-C allele score adjusted for triglycerides, LDL-C, or statin use (OR: 0.81; 95% CI: 0.44, 1.46) showed a robust association. For triglycerides, the unrestricted allele score (67 SNPs) and the restricted allele score (27 SNPs) were both associated with CHD (OR: 1.62; 95% CI: 1.24, 2.11 and 1.61; 95% CI: 1.00, 2.59, respectively) per 1-log unit increment. However, the unrestricted triglyceride score adjusted for HDL-C, LDL-C, and statin use gave an OR for CHD of 1.01 (95% CI: 0.59, 1.75). Conclusion The genetic findings support a causal effect of triglycerides on CHD risk, but a causal role for HDL-C, though possible, remains less certain.
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| 17. |
- Li, Zhe, 1987-
(author)
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Fate of Pharmaceuticals and Their Transformation Products in Rivers : An integration of target analysis and screening methods to study attenuation processes
- 2015
-
Doctoral thesis (other academic/artistic)abstract
- Pharmaceuticals are environmental contaminants causing steadily increasing concern due to their high usage, ubiquitous distribution in the aquatic environment, and potential to exert adverse effects on the ecosystems. After being discharged from wastewater treatment plants (WWTPs), pharmaceuticals can undergo transformation processes in surface waters, of which microbial degradation in river sediments is considered highly significant. In spite of a substantial number of studies on the occurrence of pharmaceuticals in aquatic systems, a comprehensive understanding of their environmental fate is still limited. First of all, very few consistent datasets from lab-based experiments to field studies exist to allow for a straightforward comparison of observations. Secondly, data on the identity and occurrence of transformation products (TPs) is insufficient and the relation of the behavior of TPs to that of their parent compounds (PCs) is poorly understood. In this thesis, these knowledge gaps were addressed by integrating the TP identification using suspect/non-target screening approaches and PC/TP fate determination. The overarching objective was to improve the understanding of the fate of pharmaceuticals in rivers, with a specific focus on water-sediment interactions, and formation and behavior of TPs. In paper I, 11 pharmaceutical TPs were identified in water-sediment incubation experiments using non-target screening. Bench-scale flume experiments were conducted in paper II to simultaneously investigate the behavior of PCs and TPs in both water and sediment compartments under more complex and realistic hydraulic conditions. The results illustrate that water-sediment interactions play a significant role for efficient attenuation of PCs, and demonstrate that TPs are formed in sediment and released back to surface water. In paper III the environmental behavior of PCs along stretches of four wastewater-impacted rivers was related to that of their TPs. The attenuation of PCs is highly compound and site specific. The highest attenuation rates of the PCs were observed in the river with the most efficient river water-pore water exchange. This research also indicates that WWTPs can be a major source of TPs to the receiving waters. In paper IV, suspect screening with a case-control concept was applied on water samples collected at both ends of the river stretches, which led to the identification of several key TPs formed along the stretches. The process-oriented strategies applied in this thesis provide a basis for prioritizing and identifying the critical PCs and TPs with respect to environmental relevance in future fate studies.
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| 18. |
- McLachlan, Michael S., et al.
(author)
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Fate of a perfluoroalkyl acid mixture in an agricultural soil studied in lysimeters
- 2019
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In: Chemosphere. - : Elsevier BV. - 0045-6535 .- 1879-1298. ; 223, s. 180-187
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Journal article (peer-reviewed)abstract
- Perfluoroalkyl acids (PFAAs) are environmental contaminants of concern in both food and drinking water. PFAA fate in agricultural soil is an important determinant of PFAA contamination of groundwater and crops. The fate of C4-C14 perfluorinated carboxylic acids (PFCAs) and two perfluorinated sulfonic acids (PFSAs) in an agricultural soil was studied in a field lysimeter experiment. Soil was spiked with PFAAs at four different levels and crops were planted. PFAA concentrations in soil were measured at the beginning and end of the growing season. Lysimeter drainage water was collected and analysed. The concentrations of all PFAAs decreased in the surface soil during the growing season, with the decrease being negatively correlated with the number of fluorinated carbons in the PFAA molecule. PFAA transfer to the drainage water was also negatively correlated with the number of fluorinated carbons. For the C11-C14 PFCAs most of the decrease in soil concentration was attributed to the formation of non-extractable residues. For the remaining PFAAs leaching was the dominant removal process. Leaching was concentration dependent, with more rapid removal from the soils spiked with higher PFAA levels. Model simulations based on measured K-d values under-predicted removal by leaching. This was attributed to mixture effects that reduced PFAA sorption to soil.
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| 19. |
- McLachlan, Michael S., et al.
(author)
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Using Model-Based Screening to Help Discover Unknown Environmental Contaminants
- 2014
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In: Environmental Science and Technology. - : American Chemical Society (ACS). - 0013-936X .- 1520-5851. ; 48:13, s. 7264-7271
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Journal article (peer-reviewed)abstract
- Of the tens of thousands of chemicals in use, only a small fraction have been analyzed in environmental samples. To effectively identify environmental contaminants, methods to prioritize chemicals for analytical method development are required. We used a high-throughput model of chemical emissions, fate, and bioaccumulation to identify chemicals likely to have high concentrations in specific environmental media, and we prioritized these for target analysis. This model-based screening was applied to 215 organosilicon chemicals culled from industrial chemical production statistics. The model-based screening prioritized several recognized organosilicon contaminants and generated hypotheses leading to the selection of three chemicals that have not previously been identified as potential environmental contaminants for target analysis. Trace analytical methods were developed, and the chemicals were analyzed in air, sewage sludge, and sediment. All three substances were found to be environmental contaminants. Phenyl-tris(trimethylsiloxy)silane was present in all samples analyzed, with concentrations of similar to 50 pg m(-3) in Stockholm air and similar to 0.5 ng g(-1) dw in sediment from the Stockholm archipelago. Tris(trifluoropropyl)trimethyl-cyclotrisiloxane and tetrakis(trifluoropropyl)tetramethyl-cyclotetrasiloxane were found in sediments from Lake Mjosa at similar to 1 ng g(-1) dw. The discovery of three novel environmental contaminants shows that models can be useful for prioritizing chemicals for exploratory assessment.
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| 20. |
- Schmidt, Amand F., et al.
(author)
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PCSK9 genetic variants and risk of type 2 diabetes : a mendelian randomisation study
- 2017
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In: The Lancet Diabetes and Endocrinology. - : ELSEVIER SCIENCE INC. - 2213-8587 .- 2213-8595. ; 5:2, s. 97-105
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Journal article (peer-reviewed)abstract
- Background Statin treatment and variants in the gene encoding HMG-CoA reductase are associated with reductions in both the concentration of LDL cholesterol and the risk of coronary heart disease, but also with modest hyperglycaemia, increased bodyweight, and modestly increased risk of type 2 diabetes, which in no way off sets their substantial benefi ts. We sought to investigate the associations of LDL cholesterol-lowering PCSK9 variants with type 2 diabetes and related biomarkers to gauge the likely eff ects of PCSK9 inhibitors on diabetes risk. Methods In this mendelian randomisation study, we used data from cohort studies, randomised controlled trials, case control studies, and genetic consortia to estimate associations of PCSK9 genetic variants with LDL cholesterol, fasting blood glucose, HbA 1c, fasting insulin, bodyweight, waist-to-hip ratio, BMI, and risk of type 2 diabetes, using a standardised analysis plan, meta-analyses, and weighted gene-centric scores. Findings Data were available for more than 550 000 individuals and 51 623 cases of type 2 diabetes. Combined analyses of four independent PCSK9 variants (rs11583680, rs11591147, rs2479409, and rs11206510) scaled to 1 mmol/L lower LDL cholesterol showed associations with increased fasting glucose (0.09 mmol/L, 95% CI 0.02 to 0.15), bodyweight (1.03 kg, 0.24 to 1.82), waist-to-hip ratio (0.006, 0.003 to 0.010), and an odds ratio for type diabetes of 1.29 (1.11 to 1.50). Based on the collected data, we did not identify associations with HbA 1c (0.03%, -0.01 to 0.08), fasting insulin (0.00%, -0.06 to 0.07), and BMI (0.11 kg/m(2), -0.09 to 0.30). Interpretation PCSK9 variants associated with lower LDL cholesterol were also associated with circulating higher fasting glucose concentration, bodyweight, and waist-to-hip ratio, and an increased risk of type 2 diabetes. In trials of PCSK9 inhibitor drugs, investigators should carefully assess these safety outcomes and quantify the risks and benefi ts of PCSK9 inhibitor treatment, as was previously done for statins.
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| 21. |
- Schmidt, Amand F., et al.
(author)
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Phenome-wide association analysis of LDL-cholesterol lowering genetic variants in PCSK9
- 2019
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In: BMC Cardiovascular Disorders. - : BMC. - 1471-2261 .- 1471-2261. ; 19:1
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Journal article (peer-reviewed)abstract
- Background: We characterised the phenotypic consequence of genetic variation at the PCSK9 locus and compared findings with recent trials of pharmacological inhibitors of PCSK9. Methods: Published and individual participant level data (300,000+ participants) were combined to construct a weighted PCSK9 gene-centric score (GS). Seventeen randomized placebo controlled PCSK9 inhibitor trials were included, providing data on 79,578 participants. Results were scaled to a one mmol/L lower LDL-C concentration. Results: The PCSK9 GS (comprising 4 SNPs) associations with plasma lipid and apolipoprotein levels were consistent in direction with treatment effects. The GS odds ratio (OR) for myocardial infarction (MI) was 0.53 (95% CI 0.42; 0.68), compared to a PCSK9 inhibitor effect of 0.90 (95% CI 0.86; 0.93). For ischemic stroke ORs were 0.84 (95% CI 0.57; 1.22) for the GS, compared to 0.85 (95% CI 0.78; 0.93) in the drug trials. ORs with type 2 diabetes mellitus (T2DM) were 1.29 (95% CI 1.11; 1.50) for the GS, as compared to 1.00 (95% CI 0.96; 1.04) for incident T2DM in PCSK9 inhibitor trials. No genetic associations were observed for cancer, heart failure, atrial fibrillation, chronic obstructive pulmonary disease, or Alzheimer's disease - outcomes for which large-scale trial data were unavailable. Conclusions: Genetic variation at the PCSK9 locus recapitulates the effects of therapeutic inhibition of PCSK9 on major blood lipid fractions and MI. While indicating an increased risk of T2DM, no other possible safety concerns were shown; although precision was moderate.
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| 22. |
- Zou, Hongyan, 1985-, et al.
(author)
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Temporal Variation of Chemical Persistence in a Swedish Lake Assessed by Benchmarking
- 2015
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In: Environmental Science and Technology. - : American Chemical Society (ACS). - 0013-936X .- 1520-5851. ; 49:16, s. 9881-9888
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Journal article (peer-reviewed)abstract
- Chemical benchmarldng was used to investigate the temporal variation of the persistence of chemical contaminants in a Swedish lake. The chemicals studied included 12 pharmaceuticals, an artificial sweetener, and an X-ray contrast agent. Measurements were conducted in late spring, late autumn, and winter. The transformation half-life in the lake could be quantified for 7 of the chemicals. It ranged from several days to hundreds of days. For 5 of the chemicals (bezafibrate, climbazole, diclofenac, furosemide, and hydrochlorothiazide), the measured persistence was lower in late spring than in late autumn. This may have been caused by lower temperatures and/or less irradiation during late autumn. The seasonality in chemical persistence contributed to changes in chemical concentrations in the lake during the year. The impact of seasonality of persistence was compared with the impact of other important variables determining concentrations in the lake: chemical inputs and water flow/dilution. The strongest seasonal variability in chemical concentration in lake water was observed for hydrochlorothiazide (over a factor of 10), and this was attributable to the seasonality in its persistence.
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| 23. |
- Zou, Hongyan, et al.
(author)
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Using Chemical Benchmarking to Determine the Persistence of Chemicals in a Swedish Lake
- 2015
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In: Environmental Science and Technology. - : American Chemical Society (ACS). - 0013-936X .- 1520-5851. ; 49:3, s. 1646-1653
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Journal article (peer-reviewed)abstract
- It is challenging to measure the persistence of chemicals under field conditions. In this work, two approaches for measuring persistence in the field were compared: the chemical mass balance approach, and a novel chemical benchmarking approach. Ten pharmaceuticals, an X-ray contrast agent, and an artificial sweetener were studied in a Swedish lake. Acesulfame K was selected as a benchmark to quantify persistence using the chemical benchmarking approach. The 95% confidence intervals of the half-life for transformation in the lake system ranged from 780-5700 days for carbamazepine to <1-2 days for ketoprofen. The persistence estimates obtained using the benchmarking approach agreed well with those from the mass balance approach (1-21% difference), indicating that chemical benchmarking can be a valid and useful method to measure the persistence of chemicals under field conditions. Compared to the mass balance approach, the benchmarking approach partially or completely eliminates the need to quantify mass flow of chemicals, so it is particularly advantageous when the quantification of mass flow of chemicals is difficult. Furthermore, the benchmarking approach allows for ready comparison and ranking of the persistence of different chemicals.
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| 24. |
- Adolfsson-Erici, Margaretha, et al.
(author)
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A flow-through passive dosing system for continuously supplying aqueous solutions of hydrophobic chemicals to bioconcentration and aquatic toxicity tests
- 2012
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In: Chemosphere. - : Elsevier BV. - 0045-6535 .- 1879-1298. ; 86:6, s. 593-599
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Journal article (peer-reviewed)abstract
- A continuous supply of water with defined stable concentrations of hydrophobic chemicals is a requirement in a range of laboratory tests such as the OECD 305 protocol for determining the bioconcentration factor in fish. Satisfying this requirement continues to be a challenge, particularly for hydrophobic chemicals. Here we present a novel solution based on equilibrium passive dosing. It employs a commercially available unit consisting of similar to 16000 polydimethylsiloxane (PDMS) tubes connected to two manifolds. The chemicals are loaded into the unit by repeatedly perfusing it with a methanol solution of the substances that is progressively diluted with water. Thereafter the unit is perfused with water and the chemicals partition from the unit into the water. The system was tested with nine chemicals with logK(ow) ranging from 4.1 to 6.3. The aqueous concentrations generated were shown to be largely independent of the water flow rate, and the unit to unit reproducibility was within a factor of similar to 2. In continuous flow experiments the aqueous concentrations of most of the study chemicals remained constant over 8 d. A model was assembled that allows prediction of the operating characteristics of the system from the logKow or PDMS/water partition coefficient of the chemical. The system is a simple, safe, predictable and flexible tool that generates stable aqueous concentrations of hydrophobic chemicals.
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| 25. |
- Adolfsson-Erici, Margaretha, 1950-
(author)
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Fish bile in environmental analysis
- 2005
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Doctoral thesis (other academic/artistic)abstract
- This work explores the usefulness of fish bile analysis in combination with biomarkers for identifying and evaluating new environmental contaminants in the aquatic environment. It illustrates how bile analysis can be used together with biomarkers to assess the causes of estrogenic effects, to identify chemicals in the aquatic environment that are taken up by fish, and to monitor environmental exposure.In a first application, fish exposed to sewage treatment plant effluent were studied. Elevated levels of vitellogenin in the exposed fish demonstrated that estrogenic effects occurred. Several estrogen disrupting substances were identified in the fish bile, and analysis of water samples confirmed that these substances were present in the effluent. The synthetic estrogen 17a-ethinylestradiol, which is known to be present in sewage treatment plant effluent, was shown for the first time to be taken up by fish. Considering the reported potencies of the detected substances, it was concluded that 17a-ethinylestradiol was the major contributor to the estrogenic effects.Chemical analysis of bile was used to identify rubber additives that were released from tires immersed in water. The bile of rainbow trout held in the water contained high levels of metabolites of PAHs and aromatic nitrogen compounds. Several biomarkers were also measured in the exposed fish, and EROD induction and oxidative stress were observed. Based on the bile analysis observations together with knowledge of toxicological mechanisms, it was postulated that the EROD induction was due to the PAHs, while aromatic nitrogen compounds caused the oxidative stress.Resin acids in fish bile proved to be a good indicator of exposure in a chronic long-term study of rainbow trout exposed to effluent from a total chlorine free (TCF) pulp mill. Elevated levels of GST (gluthatione-S-transferase) and GR (gluthatione reductase) activity, and the presence of DNA adducts after a two month recovery period, indicated that compounds in the pulp mill effluents have persistent effects. In addition to characterising the exposure of the fish to the effluent, the analysis of the resin acids in the bile provided evidence of accidents in the pulp mill that the existing process monitoring system had not detected.Resin acids in bile were also found to be a valuable indicator of exposure to pulp mill effluents for eelpout living in the Baltic Sea. A correlation between resin acid levels in bile and skewed sex ratios provided an important link in the chain of evidence that substances in the pulp mill effluents cause male bias of the eelpout embryos.A particularly good example of the potential of bile analysis was the identification of a previously unknown environmental contaminant. A large peak was observed in the bile extracts of fish that had been exposed to sewage treatment plant effluent. This peak was identified as triclosan, which demonstrated its presence in sewage treatment plant effluent. Other work went on to show that it is a common contaminant of the aquatic environment. The ability of fish to concentrate contaminant metabolites in bile to levels very much higher than in the environment, and the comparatively low levels of analytic interferences, make bile a particularly attractive matrix to search for new, unknown organic pollutants
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