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- Horne, B D, et al.
(author)
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Pharmacogenetic warfarin dose refinements remain significantly influenced by genetic factors after one week of therapy
- 2012
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In: Thrombosis and Haemostasis. - 0340-6245 .- 2567-689X. ; 107:2, s. 232-240
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Journal article (peer-reviewed)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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- Karmin, Monika, et al.
(author)
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A recent bottleneck of Y chromosome diversity coincides with a global change in culture.
- 2015
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In: Genome Research. - : Cold Spring Harbor Laboratory. - 1088-9051 .- 1549-5469. ; 25:4
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Journal article (peer-reviewed)abstract
- It is commonly thought that human genetic diversity in non-African populations was shaped primarily by an out-of-Africa dispersal 50-100 thousand yr ago (kya). Here, we present a study of 456 geographically diverse high-coverage Y chromosome sequences, including 299 newly reported samples. Applying ancient DNA calibration, we date the Y-chromosomal most recent common ancestor (MRCA) in Africa at 254 (95% CI 192-307) kya and detect a cluster of major non-African founder haplogroups in a narrow time interval at 47-52 kya, consistent with a rapid initial colonization model of Eurasia and Oceania after the out-of-Africa bottleneck. In contrast to demographic reconstructions based on mtDNA, we infer a second strong bottleneck in Y-chromosome lineages dating to the last 10 ky. We hypothesize that this bottleneck is caused by cultural changes affecting variance of reproductive success among males.
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- Lorenzen, Eline D., et al.
(author)
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Species-specific responses of Late Quaternary megafauna to climate and humans
- 2011
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In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 479:7373, s. 359-364
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Journal article (peer-reviewed)abstract
- Despite decades of research, the roles of climate and humans in driving the dramatic extinctions of large-bodied mammals during the Late Quaternary period remain contentious. Here we use ancient DNA, species distribution models and the human fossil record to elucidate how climate and humans shaped the demographic history of woolly rhinoceros, woolly mammoth, wild horse, reindeer, bison and musk ox. We show that climate has been a major driver of population change over the past 50,000 years. However, each species responds differently to the effects of climatic shifts, habitat redistribution and human encroachment. Although climate change alone can explain the extinction of some species, such as Eurasian musk ox and woolly rhinoceros, a combination of climatic and anthropogenic effects appears to be responsible for the extinction of others, including Eurasian steppe bison and wild horse. We find no genetic signature or any distinctive range dynamics distinguishing extinct from surviving species, emphasizing the challenges associated with predicting future responses of extant mammals to climate and human-mediated habitat change.
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- Borjesson, A, et al.
(author)
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Male Anabolic Androgenic Steroid Users with Personality Disorders Report More Aggressive Feelings, Suicidal Thoughts, and Criminality
- 2020
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In: Medicina (Kaunas, Lithuania). - : MDPI AG. - 1648-9144. ; 56:6
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Journal article (peer-reviewed)abstract
- Background and objectives: Anabolic androgenic steroids (AAS) are mainly used for aesthetic and performance-enhancing reasons. Their use is a growing public health problem and concern for society because of their adverse effects. The primary aim of this study was to identify psychiatric and personality disorders and to measure anxiety and depression in AAS users. Materials and Methods: Fifty-six males who actively contacted the Anti-Doping Hot-Line and wished to stop using AAS were included. Structured Clinical Interviews Diagnosis-I and -II were used to diagnose psychiatric and personality disorders. The Brief Scale for Anxiety and Montgomery Asberg Depression Rating Scale (subscales from the Comprehensive Psychopathological Rating Scale) were used to measure changes in anxiety and depression. Structured Clinical Interviews Diagnosis-I and -II were performed at one time point. Anxiety and depression were measured at inclusion and after six months. Urine samples were collected for an analysis of AAS and drugs of abuse. Results: All participants reported some adverse effects that they associated with AAS use. In total, 56% and 52% of the cohort fulfilled the criteria for Structured Clinical Interviews Diagnosis-I and -II diagnoses, respectively. A significantly increased risk of reporting aggressive feelings/behaviors (Odds Ratio (OR) = 4.9; Confidence Interval (CI) 0.99–25, p = 0.04), suicidal thoughts/attempts (OR = 4.6, CI 95; 0.99–21, p = 0.04) and criminality (OR = 6.5, CI 1–39, p = 0.03) was found among individuals with AAS use fulfilling the criteria for personality disorders compared with those without such AAS use. The Brief Scale for Anxiety score decreased from the median of 15 at inclusion to 10 at the follow-up visit six months later (p = 0.01, n = 19). Conclusions: Our findings indicate that among individuals with AAS use, those with a personality disorder report more aggressive behaviors, suicidal thoughts/suicidal attempts, and criminality than those without a personality disorder.
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