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- Horne, B D, et al.
(författare)
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Pharmacogenetic warfarin dose refinements remain significantly influenced by genetic factors after one week of therapy
- 2012
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Ingår i: Thrombosis and Haemostasis. - 0340-6245 .- 2567-689X. ; 107:2, s. 232-240
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Tidskriftsartikel (refereegranskat)abstract
- By guiding initial warfarin dose, pharmacogenetic (PGx) algorithms may improve the safety of warfarin initiation. However, once international normalised ratio (INR) response is known, the contribution of PGx to dose refinements is uncertain. This study sought to develop and validate clinical and PGx dosing algorithms for warfarin dose refinement on days 6-11 after therapy initiation. An international sample of 2,022 patients at 13 medical centres on three continents provided clinical, INR, and genetic data at treatment days 6-11 to predict therapeutic warfarin dose. Independent derivation and retrospective validation samples were composed by randomly dividing the population (80%/20%). Prior warfarin doses were weighted by their expected effect on S-warfarin concentrations using an exponential-decay pharmacokinetic model. The INR divided by that "effective" dose constituted a treatment response index . Treatment response index, age, amiodarone, body surface area, warfarin indication, and target INR were associated with dose in the derivation sample. A clinical algorithm based on these factors was remarkably accurate: in the retrospective validation cohort its R2 was 61.2% and median absolute error (MAE) was 5.0 mg/week. Accuracy and safety was confirmed in a prospective cohort (N=43). CYP2C9 variants and VKORC1-1639 G→A were significant dose predictors in both the derivation and validation samples. In the retrospective validation cohort, the PGx algorithm had: R2= 69.1% (p<0.05 vs. clinical algorithm), MAE= 4.7 mg/week. In conclusion, a pharmacogenetic warfarin dose-refinement algorithm based on clinical, INR, and genetic factors can explain at least 69.1% of therapeutic warfarin dose variability after about one week of therapy.
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| 2. |
- Bergkvist, C., et al.
(författare)
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Dietary exposure to polychlorinated biphenyls is associated with increased risk of stroke in women
- 2014
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Ingår i: Journal of Internal Medicine. - : WILEY. - 0954-6820 .- 1365-2796. ; 276:3, s. 248-259
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Tidskriftsartikel (refereegranskat)abstract
- Objective. The potentially beneficial effects of fish consumption on stroke may be modified by major food contaminants in fish. Polychlorinated biphenyls (PCBs) in particular are proposed to play a role in the aetiology of stroke. The aim of this study was to assess the association between dietary PCB exposure and stroke risk with the intake of long-chain omega-3 fish fatty acids and fish consumption. Design. The prospective population-based Swedish Mammography Cohort was examined. It was comprised of 34 591 women free of cardiovascular diseases and cancer at baseline in 1997 and followed up for 12 years. Validated estimates of dietary PCB exposure were obtained via a food frequency questionnaire at baseline. Incident cases of stroke were ascertained through register linkage. Results. During 12 years of follow-up (397 309 person-years), there were 2015 incident cases of total stroke (1532 ischaemic strokes, 216 intracerebral haemorrhages, 94 subarachnoid haemorrhages and 173 unspecified strokes). Multivariable-adjusted relative risks (RR), controlled for known stroke risk factors and fish consumption, were 1.67 [95% confidence interval (CI), 1.29-2.17] for total stroke, 1.61 (95% CI, 1.19-2.17) for ischaemic stroke and 2.80 (95% CI, 1.42-5.55) for haemorrhagic stroke for women in the highest quartile of dietary PCB exposure (median 288 ng day(-1)) compared with women in the lowest quartile (median 101 ng day(-1)). Conclusion. Dietary exposure to PCBs was associated with an increased stroke risk in women, especially haemorrhagic stroke. The results provide important information regarding the risk-benefit analysis of fish consumption, particularly for cerebrovascular disease prevention.
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| 6. |
- Darnerud, P. O., et al.
(författare)
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POP levels in breast milk and maternal serum and thyroid hormone levels in mother-child pairs from Uppsala, Sweden
- 2010
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Ingår i: Environment International. - : Elsevier BV. - 0160-4120 .- 1873-6750. ; 36:2, s. 180-187
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Tidskriftsartikel (refereegranskat)abstract
- In experimental studies, it has frequently been observed that the homeostasis of thyroid hormones (THs) is affected by exposure to persistent organic pollutants (POPs), such as dioxins and PCBs. In man, similar effects have been indicated in several epidemiological studies. In order to investigate the possible effect on THs at low background exposures found among the Swedish population the following study was performed. Primiparous women (n=395) in the Uppsala region were recruited between 1996 and 1999. Of these, 325 mothers agreed to donate a serum sample in late pregnancy and breast milk was obtained from 211 women 3 weeks after delivery. Babies were sampled for blood at 3 weeks (n=150) and 3 months (n=115) after birth. In connection to the sampling, questions on personal characteristics were asked. Levels of low (tri- to penta-) chlorinated PCB, di-ortho PCB, p,p'-DDE, (mono-ortho) PCB TEQ and PCDD/DF TEQ were monitored in breast milk and in mother's blood (not PCDD/DF). The results showed that the measured TH levels (thyroid-stimulating hormone - TSH, total tri-iodothyronine - TT3, free thyroxine - FT4) in mothers and children were within the reference range. Some significant associations were seen between POP exposures and TH levels in mother or child after simple regression analysis. Following adjustment for important confounding factors, the significant associations mostly disappeared. However, significantly decreasing TT3 levels with increasing prenatal low-chlorinated PCB exposure were still seen in 3 week old children, and on TT3 in mothers exposed to PCDD/DF. In conclusion, the study clearly shows the importance of adjustment for important confounding factors in the analysis of possible associations between POP exposure and hormonal effects. The remaining associations are weak in both children and mothers and the clinical consequences of these alterations are uncertain. When comparing studies that investigate associations between TH levels and POP levels during the perinatal stage, no obvious between-study concordance was seen regarding the critical dose for hormonal effects to occur.
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