Metabolic processes can influence disease risk and provide therapeutic targets. By conducting genome-wide association studies of 1,091 blood metabolites and 309 metabolite ratios, we identified ...associations with 690 metabolites at 248 loci and associations with 143 metabolite ratios at 69 loci. Integrating metabolite-gene and gene expression information identified 94 effector genes for 109 metabolites and 48 metabolite ratios. Using Mendelian randomization (MR), we identified 22 metabolites and 20 metabolite ratios having estimated causal effect on 12 traits and diseases, including orotate for estimated bone mineral density, α-hydroxyisovalerate for body mass index and ergothioneine for inflammatory bowel disease and asthma. We further measured the orotate level in a separate cohort and demonstrated that, consistent with MR, orotate levels were positively associated with incident hip fractures. This study provides a valuable resource describing the genetic architecture of metabolites and delivers insights into their roles in common diseases, thereby offering opportunities for therapeutic targets.
Abstract
Context
It is important to identify patients at highest risk of fractures.
Objective
To compare the separate and combined performances of bone-related genetic risk scores (GRSs) for ...prediction of forearm, hip and vertebral fractures separately, as well as of trabecular and cortical bone microstructure parameters separately.
Design, Setting, and Participants
Using 1103 single nucleotide polymorphisms (SNPs) independently associated with estimated bone mineral density of the heel (eBMD), we developed a weighted GRS for eBMD and determined its contribution to fracture prediction beyond 2 previously developed GRSs for femur neck BMD (49 SNPs) and lumbar spine BMD (48 SNPs). Associations between these GRSs and forearm (ncases = 1020; ncontrols = 2838), hip (ncases = 1123; ncontrols = 2630) and vertebral (ncases = 288; ncontrols = 1187) fractures were evaluated in 3 Swedish cohorts. Associations between the GRSs and trabecular and cortical bone microstructure parameters (n = 426) were evaluated in the MrOS Sweden cohort.
Results
We found that eBMDGRS was the only significant independent predictor of forearm and vertebral fractures while both FN-BMDGRS and eBMDGRS were significant independent predictors of hip fractures. The eBMDGRS was the major GRS contributing to prediction of trabecular bone microstructure parameters while both FN-BMDGRS and eBMDGRS contributed information for prediction of cortical bone microstructure parameters.
Conclusions
The eBMDGRS independently predicts forearm and vertebral fractures while both FN-BMDGRS and eBMDGRS contribute independent information for prediction of hip fractures. We propose that eBMDGRS captures unique information about trabecular bone microstructure useful for prediction of forearm and vertebral fractures. These findings may facilitate personalized medicine to predict site-specific fractures as well as cortical and trabecular bone microstructure separately.
Smoking is known to be a major cause of death among middle-aged adults, but evidence on its impact and the benefits of smoking cessation among older adults has remained limited. Therefore, we aimed ...to estimate the influence of smoking and smoking cessation on all-cause mortality in people aged ≥60 years.
Relative mortality and mortality rate advancement periods (RAPs) were estimated by Cox proportional hazards models for the population-based prospective cohort studies from Europe and the U.S. (CHANCES Consortium on Health and Ageing: Network of Cohorts in Europe and the U.S.), and subsequently pooled by individual participant meta-analysis. Statistical analyses were performed from June 2013 to March 2014.
A total of 489,056 participants aged ≥60 years at baseline from 22 population-based cohort studies were included. Overall, 99,298 deaths were recorded. Current smokers had 2-fold and former smokers had 1.3-fold increased mortality compared with never smokers. These increases in mortality translated to RAPs of 6.4 (95% CI=4.8, 7.9) and 2.4 (95% CI=1.5, 3.4) years, respectively. A clear positive dose-response relationship was observed between number of currently smoked cigarettes and mortality. For former smokers, excess mortality and RAPs decreased with time since cessation, with RAPs of 3.9 (95% CI=3.0, 4.7), 2.7 (95% CI=1.8, 3.6), and 0.7 (95% CI=0.2, 1.1) for those who had quit <10, 10 to 19, and ≥20 years ago, respectively.
Smoking remains as a strong risk factor for premature mortality in older individuals and cessation remains beneficial even at advanced ages. Efforts to support smoking abstinence at all ages should be a public health priority.
Att behandla med läkemedel är en kärnuppgift för läkare; grundutbildningen behöver ge studenterna förutsättningar att klara detta.
Enkätresultat från fyra lärosäten visade att 45 procent av ...studenterna efter sin invärtesmedicinska placering kände sig trygga med att göra läkemedelsgenomgångar och 62 procent med att skriva läkemedelsberättelser.
Studenter som gör många läkemedelsgenomgångar/läkemedelsberättelser känner större trygghet och reflekterar mer över patientens behandling.
Klinisk handledning gör skillnad.
När kursplaner revideras vid införandet av en sexårig läkarutbildning, med förskrivningsrätt direkt efter examen, behöver klinisk träning i läkemedelsarbete inklusive handledning tydliggöras.
A prerequisite for rational use of medicines is adequate prescribing skills; drug treatment is a complex task requiring diagnostic competence combined with pharmacologic knowledge and patient communication skills. Acquiring professional confidence in the art of prescribing is essential during medical training. The results of this questionnaire study, conducted in four medical schools in Sweden after the course in internal medicine (252 respondents; response rate: 74%; median age: 24 years, 61% female), show that 45% and 62% were confident in performing medication reviews and writing medication summary reports, respectively, i.e. the basics of prescribing. The confidence increased by the number of reviews and reports performed, i.e. the extent of practice (correlation coefficients: 0.41 and 0.38, respectively, both p<0.0001), as did the extent of the students' reflection on important aspects of drug treatment such as adherence, adverse reactions, renal function, dosing, and drug interactions. In multivariate regression analyses, major predictors for confidence in performing medication reviews were extent of practice and extent of clinical supervision. The results suggest that these factors are keys to acquiring professional confidence in the art of prescribing.
Even though vitamin D is mainly produced by exposure to sunlight, little is known regarding vitamin D levels in populations living in sub-Arctic areas with little or no daylight during winter.
We ...describe distributions of vitamin D3 and the prevalence of adequate levels in a population living above 63°N.
We sampled 1,622 randomly selected subjects, aged 25-74 years, between January and May, 2009, as part of the Northern Sweden MONICA study (69.2% participation rate). By using HPLC, 25(OH) vitamin D3 was analysed. Levels used for definitions were deficient, D3<25 nmol/l (<10 ng/ml); insufficient, D3 25-49.9 nmol/l (10-20 ng/ml); and adequate, D3≥50 nmol/l (20 ng/ml).
Mean (median) level of vitamin D3 was 65.2 (63.6) nmol/l in men and 71.0 (67.7) nmol/l in women. Adequate levels were found in 79.2%, more often in women (82.7%) than in men (75.6%). Only 0.7% of the population were vitamin D3-deficient but 23.1% of men and 17.1% of women had insufficient levels. Levels of vitamin D3 increased with age and insufficient status was most common among those aged 25-34 years, 41.0% in men and 22.3% in women.
If subjects using vitamin D-supplementation are excluded, the population level of D3 is 1-2 nmol/l lower than in the general population across sex- and age groups. There were no differences between the northern or the southern parts, between urban or rural living or according to educational attainment. Those subjects born outside of Sweden or Finland had lower levels.
The large majority living close to the Arctic Circle in Sweden have adequate D3 levels even during the second half of the dark winter. Subjects with D3 deficiency were uncommon but insufficient levels were often found among young men.
PDF
