| 1. |
- Joshi, Peter K, et al.
(författare)
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Directional dominance on stature and cognition in diverse human populations
- 2015
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 523:7561, s. 459-462
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Tidskriftsartikel (refereegranskat)abstract
- Homozygosity has long been associated with rare, often devastating, Mendelian disorders, and Darwin was one of the first to recognize that inbreeding reduces evolutionary fitness. However, the effect of the more distant parental relatedness that is common in modern human populations is less well understood. Genomic data now allow us to investigate the effects of homozygosity on traits of public health importance by observing contiguous homozygous segments (runs of homozygosity), which are inferred to be homozygous along their complete length. Given the low levels of genome-wide homozygosity prevalent in most human populations, information is required on very large numbers of people to provide sufficient power. Here we use runs of homozygosity to study 16 health-related quantitative traits in 354,224 individuals from 102 cohorts, and find statistically significant associations between summed runs of homozygosity and four complex traits: height, forced expiratory lung volume in one second, general cognitive ability and educational attainment (P < 1 × 10(-300), 2.1 × 10(-6), 2.5 × 10(-10) and 1.8 × 10(-10), respectively). In each case, increased homozygosity was associated with decreased trait value, equivalent to the offspring of first cousins being 1.2 cm shorter and having 10 months' less education. Similar effect sizes were found across four continental groups and populations with different degrees of genome-wide homozygosity, providing evidence that homozygosity, rather than confounding, directly contributes to phenotypic variance. Contrary to earlier reports in substantially smaller samples, no evidence was seen of an influence of genome-wide homozygosity on blood pressure and low density lipoprotein cholesterol, or ten other cardio-metabolic traits. Since directional dominance is predicted for traits under directional evolutionary selection, this study provides evidence that increased stature and cognitive function have been positively selected in human evolution, whereas many important risk factors for late-onset complex diseases may not have been.
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| 2. |
- Ademuyiwa, Adesoji O., et al.
(författare)
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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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Ingår i: BMJ Global Health. - : BMJ Publishing Group Ltd. - 2059-7908. ; 1:4
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Tidskriftsartikel (refereegranskat)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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| 3. |
- Kato, Norihiro, et al.
(författare)
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Trans-ancestry genome-wide association study identifies 12 genetic loci influencing blood pressure and implicates a role for DNA methylation
- 2015
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Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 47:11, s. 1282-1293
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Tidskriftsartikel (refereegranskat)abstract
- We carried out a trans-ancestry genome-wide association and replication study of blood pressure phenotypes among up to 320,251 individuals of East Asian, European and South Asian ancestry. We find genetic variants at 12 new loci to be associated with blood pressure (P = 3.9 × 10−11 to 5.0 × 10−21). The sentinel blood pressure SNPs are enriched for association with DNA methylation at multiple nearby CpG sites, suggesting that, at some of the loci identified, DNA methylation may lie on the regulatory pathway linking sequence variation to blood pressure. The sentinel SNPs at the 12 new loci point to genes involved in vascular smooth muscle (IGFBP3, KCNK3, PDE3A and PRDM6) and renal (ARHGAP24, OSR1, SLC22A7 and TBX2) function. The new and known genetic variants predict increased left ventricular mass, circulating levels of NT-proBNP, and cardiovascular and all-cause mortality (P = 0.04 to 8.6 × 10−6). Our results provide new evidence for the role of DNA methylation in blood pressure regulation.
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| 4. |
- Holmes, Naomi, et al.
(författare)
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Climatic variability during the last millennium in Western Iceland from lake sediment records
- 2016
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Ingår i: The Holocene. - : SAGE Publications. - 0959-6836 .- 1477-0911. ; 26:5, s. 756-771
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Tidskriftsartikel (refereegranskat)abstract
- The aim of this research was to create a decadal-scale terrestrial quantitative palaeoclimate record for NW Iceland from lake sediments for the last millennium. Geochemical, stable isotope and chironomid reconstructions were obtained from a lake sequence constrained by tephra deposits on the Snaefellsnes peninsula, western Iceland. Obtaining a quantitative record proved problematic, but the qualitative chironomid record showed clear trends associated with past summer temperatures, and the sedimentological records provided evidence for past changes in precipitation, mediated through catchment soil in-wash. When the full range of chronological uncertainty is considered, four clear phases of climatic conditions were identified: (1) a relatively warm phase between AD 1020 and 1310; (2) a relatively stable period between AD 1310 and 1510, cooler than the preceding period but still notably warmer than the second half of the millennium; (3) a consistent reduction of temperatures between AD 1560 and 1810, with the coolest period between AD 1680 and 1810; and (4) AD 1840-2000 has temperatures mainly warmer than in the preceding two centuries, with a rising trend and increased variability from c. AD 1900 onwards. The reconstructions show clearly that the first half of the millennium experienced warmer climatic conditions than the second half, with a return to the warmer climate only occurring in the last c. 100 years. Much of the variability of the chironomid record can be linked to changes in the North Atlantic Oscillation (NAO). The reconstructions presented can track low-frequency and long-term trends effectively and consistently but high-resolution and calibrated quantitative records remain more of a challenge - not just in finding optimal sedimentary deposits but also in finding the most reliable proxy. It is this that presents the real challenge for Holocene climate reconstruction from this key area of the North Atlantic.
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| 5. |
- Huffman, Jennifer E., et al.
(författare)
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Modulation of Genetic Associations with Serum Urate Levels by Body-Mass-Index in Humans
- 2015
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 10:3
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Tidskriftsartikel (refereegranskat)abstract
- We tested for interactions between body mass index (BMI) and common genetic variants affecting serum urate levels, genome-wide, in up to 42569 participants. Both stratified genome-wide association (GWAS) analyses, in lean, overweight and obese individuals, and regression-type analyses in a non BMI-stratified overall sample were performed. The former did not uncover any novel locus with a major main effect, but supported modulation of effects for some known and potentially new urate loci. The latter highlighted a SNP at RBFOX3 reaching genome-wide significant level (effect size 0.014, 95% CI 0.008-0.02, P-inter= 2.6 x 10(-8)). Two top loci in interaction term analyses, RBFOX3 and ERO1LB-EDAR-ADD, also displayed suggestive differences in main effect size between the lean and obese strata. All top ranking loci for urate effect differences between BMI categories were novel and most had small magnitude but opposite direction effects between strata. They include the locus RBMS1-TANK (men, Pdifflean-overweight= 4.7 x 10(-8)), a region that has been associated with several obesity related traits, and TSPYL5 (men, Pdifflean-overweight= 9.1 x 10(-8)), regulating adipocytes-produced estradiol. The top-ranking known urate loci was ABCG2, the strongest known gout risk locus, with an effect halved in obese compared to lean men (Pdifflean-obese= 2 x 10(-4)). Finally, pathway analysis suggested a role for N-glycan biosynthesis as a prominent urate-associated pathway in the lean stratum. These results illustrate a potentially powerful way to monitor changes occurring in obesogenic environment.
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| 6. |
- Lim, Lee Ling, et al.
(författare)
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Aspects of Multicomponent Integrated Care Promote Sustained Improvement in Surrogate Clinical Outcomes: A Systematic Review and Meta-analysis.
- 2018
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Ingår i: Diabetes care. - : American Diabetes Association. - 1935-5548 .- 0149-5992. ; 41:6, s. 1312-1320
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Tidskriftsartikel (refereegranskat)abstract
- The implementation of the Chronic Care Model (CCM) improves health care quality. We examined the sustained effectiveness of multicomponent integrated care in type 2 diabetes.We searched PubMed and Ovid MEDLINE (January 2000-August 2016) and identified randomized controlled trials comprising two or more quality improvement strategies from two or more domains (health system, health care providers, or patients) lasting ≥12 months with one or more clinical outcomes. Two reviewers extracted data and appraised the reporting quality.In a meta-analysis of 181 trials (N = 135,112), random-effects modeling revealed pooled mean differences in HbA1c of -0.28% (95% CI -0.35 to -0.21) (-3.1 mmol/mol [-3.9 to -2.3]), in systolic blood pressure (SBP) of -2.3 mmHg (-3.1 to -1.4), in diastolic blood pressure (DBP) of -1.1 mmHg (-1.5 to -0.6), and in LDL cholesterol (LDL-C) of -0.14 mmol/L (-0.21 to -0.07), with greater effects in patients with LDL-C ≥3.4 mmol/L (-0.31 vs. -0.10 mmol/L for <3.4 mmol/L; Pdifference = 0.013), studies from Asia (HbA1c -0.51% vs. -0.23% for North America [-5.5 vs. -2.5 mmol/mol]; Pdifference = 0.046), and studies lasting >12 months (SBP -3.4 vs. -1.4 mmHg, Pdifference = 0.034; DBP -1.7 vs. -0.7 mmHg, Pdifference = 0.047; LDL-C -0.21 vs. -0.07 mmol/L for 12-month studies, Pdifference = 0.049). Patients with median age <60 years had greater HbA1c reduction (-0.35% vs. -0.18% for ≥60 years [-3.8 vs. -2.0 mmol/mol]; Pdifference = 0.029). Team change, patient education/self-management, and improved patient-provider communication had the largest effect sizes (0.28-0.36% [3.0-3.9 mmol/mol]).Despite the small effect size of multicomponent integrated care (in part attenuated by good background care), team-based care with better information flow may improve patient-provider communication and self-management in patients who are young, with suboptimal control, and in low-resource settings.
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| 7. |
- Yates, Thomas, et al.
(författare)
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Association of walking pace and handgrip strength with all-cause, cardiovascular, and cancer mortality : a UK Biobank observational study
- 2017
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Ingår i: European Heart Journal. - : OXFORD UNIV PRESS. - 0195-668X .- 1522-9645. ; 38:43, s. 3232-3240
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Tidskriftsartikel (refereegranskat)abstract
- To quantify the association of self-reported walking pace and handgrip strength with all-cause, cardiovascular, and cancer mortality. A total of 230 670 women and 190 057 men free from prevalent cancer and cardiovascular disease were included from UK Biobank. Usual walking pace was self-defined as slow, steady/average or brisk. Handgrip strength was assessed by dynamometer. Cox-proportional hazard models were adjusted for social deprivation, ethnicity, employment, medications, alcohol use, diet, physical activity, and television viewing time. Interaction terms investigated whether age, body mass index (BMI), and smoking status modified associations. Over 6.3 years, there were 8598 deaths, 1654 from cardiovascular disease and 4850 from cancer. Associations of walking pace with mortality were modified by BMI. In women, the hazard ratio (HR) for all-cause mortality in slow compared with fast walkers were 2.16 [95% confidence interval (CI): 1.68-2.77] and 1.31 (1.08-1.60) in the bottom and top BMI tertiles, respectively; corresponding HRs for men were 2.01 (1.68-2.41) and 1.41 (1.20-1.66). Hazard ratios for cardiovascular mortality remained above 1.7 across all categories of BMI in men and women, with modest heterogeneity in men. Handgrip strength was associated with cardiovascular mortality in men only (HR tertile 1 vs. tertile 3 = 1.38; 1.18-1.62), without differences across BMI categories, while associations with all-cause mortality were only seen in men with low BMI. Associations for walking pace and handgrip strength with cancer mortality were less consistent. A simple self-reported measure of slow walking pace could aid risk stratification for all-cause and cardiovascular mortality within the general population.
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