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- Kapoor, Pooja Middha, et al.
(författare)
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Combined associations of a polygenic risk score and classical risk factors with breast cancer risk
- 2021
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Ingår i: Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 0027-8874 .- 1460-2105. ; 113:3, s. 329-337
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Tidskriftsartikel (refereegranskat)abstract
- We evaluated the joint associations between a new 313-variant PRS (PRS313) and questionnaire-based breast cancer risk factors for women of European ancestry, using 72 284 cases and 80 354 controls from the Breast Cancer Association Consortium. Interactions were evaluated using standard logistic regression and a newly developed case-only method for breast cancer risk overall and by estrogen receptor status. After accounting for multiple testing, we did not find evidence that per-standard deviation PRS313 odds ratio differed across strata defined by individual risk factors. Goodness-of-fit tests did not reject the assumption of a multiplicative model between PRS313 and each risk factor. Variation in projected absolute lifetime risk of breast cancer associated with classical risk factors was greater for women with higher genetic risk (PRS313 and family history) and, on average, 17.5% higher in the highest vs lowest deciles of genetic risk. These findings have implications for risk prevention for women at increased risk of breast cancer.
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| 2. |
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| 3. |
- Daebes, HL, et al.
(författare)
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Association between triage level and outcomes at Médecins Sans Frontières trauma hospital in Kunduz, Afghanistan, 2015
- 2021
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Ingår i: Emergency medicine journal : EMJ. - : BMJ. - 1472-0213 .- 1472-0205. ; 39:8, s. 628-633
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Tidskriftsartikel (refereegranskat)abstract
- Five million people die annually due to injuries; an increasing part is due to armed conflict in low-income and middle-income countries, demanding resolute emergency trauma care. In Afghanistan, a low-income country that has experienced conflict for over 35 years, conflict related trauma is a significant public health problem. To address this, the non-governmental organisation Médecins Sans Frontières (MSF) set up a trauma centre in Kunduz (Kunduz Trauma Centre (KTC)). MSF’s standardised emergency operating procedures include the South African Triage Scale (SATS). To date, there are few studies that assess how triage levels correspond with outcome in low-resource conflict settingsAimThis study aims to assess to what extent SATS triage levels correlated to outcomes in terms of hospital admission, intensive care unit (ICU) admission and mortality for patients treated at KTC.Method and materialsThis retrospective study used routinely collected data from KTC registries. A total of 17 970 patients were included. The outcomes were hospital admission, ICU admission and mortality. The explanatory variable was triage level. Covariates including age, gender and delay to arrival were used. Logistic regression was used to study the correlation between triage level and outcomes.ResultsOut of all patients seeking care, 28.7% were triaged as red or orange. The overall mortality was 0.6%. In total, 90% of those that died and 79% of ICU-admitted patients were triaged as red.ConclusionThe risk of positive and negative outcomes correlated with triage level. None of the patients triaged as green died or were admitted to the ICU whereas 90% of patients who died were triaged as red.
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| 4. |
- Forslund, Josefin M. E., 1988-
(författare)
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The consequences of DNA lesions for mitochondrial DNA maintenance
- 2021
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Eukaryotic cells have their own energy-producing organelles called mitochondria. The energy is stored in the adenosine triphosphate (ATP) molecule and is produced via the oxidative phosphorylation process inside the mitochondria. Thirteen of the essential proteins required for this process are encoded on the mitochondrial DNA (mtDNA). To ensure sufficient energy production it is therefore important to maintain mtDNA integrity. MtDNA maintenance is dependent on several factors, which include the replicative DNA polymerase. In humans, the main mitochondrial polymerase is DNA polymerase gamma (Pol γ), whereas in S. cerevisiae the homolog is called Mip1. Defects in the mitochondrial DNA polymerase and mtDNA replication in general cause mitochondrial dysfunction, reduced energy production and, in humans, mitochondrial diseases. DNA damage and non-standard nucleotides are frequently forming obstacles to the DNA replication machinery. One of the proteins that assists the nuclear replication machinery in dealing with DNA damage is the primase-polymerase PrimPol, performing either translesion DNA synthesis or alternatively priming replication restart after DNA damage. More recently, PrimPol was also identified inside the mitochondria. We therefore investigated the potential role of PrimPol to assist the mtDNA replication machinery at the site of mtDNA damage. Our results suggest that PrimPol does not work as a conventional translesion DNA polymerase at oxidative damage in the mitochondria, but instead interacts with the mtDNA replication machinery to support restart after replication stalling.Stalling of DNA replication can also occur at wrongly inserted nucleotides. In this study, we pay extra attention to ribonucleotides, which are non-standard nucleotides in the context of DNA. Ribonucleotides (rNTPs) are normally building blocks for RNA but are occasionally utilized by DNA polymerases during DNA replication. Ribonucleotides are more reactive compared to dNTPs as they have an additional hydroxyl group (-OH). Their presence in the genome can lead to replication stress and genomic instability. In nuclear DNA, ribonucleotides are efficiently removed by the Ribonucleotide Excision Repair (RER) pathway and failure to remove them leads to human disease (e.g., Aicardi-Goutières syndrome). We investigated if ribonucleotides are removed from mtDNA and if not, how the replication machinery can tolerate the presence of ribonucleotides in the mtDNA. By using several yeast strains with altered dNTP pools, we found that the RER pathway is not active in mitochondria. Instead, mitochondria have an innate tolerance to ribonucleotide incorporation in mtDNA and under normal cellular conditions mature human mtDNA contains ~50 ribonucleotides per genome. We show that this ribonucleotide tolerance is the result of human Pol γ’s remarkable abilities to 1) efficiently bypass ribonucleotides in the DNA template and 2) proficiently discriminate against the incorporation of free ribonucleotides during mtDNA replication. Pol γ’s discrimination capability against free ribonucleotides comes with a price. In the presence of high rNTP levels, Pol γ is inhibited in DNA synthesis and could eventually lead to frequent replication stalling. Together, these studies are in line with our hypothesis that ribonucleotides in mtDNA can be tolerated, with the consequence that mtDNA replication is in particular vulnerable to imbalances in rNTP/dNTP ratios.In summary, this study shows that we cannot simply extrapolate our knowledge of nuclear DNA replication stress management to the mtDNA maintenance, highlighting the need to study the molecular mechanism by which the mtDNA replication machinery is able to cope with DNA lesions to prevent loss of mtDNA integrity and disease development.
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| 5. |
- Mudie, Deanna M., et al.
(författare)
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Selection of In Vivo Predictive Dissolution Media Using Drug Substance and Physiological Properties
- 2020
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Ingår i: AAPS Journal. - : SPRINGER. - 1550-7416. ; 22:2
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Tidskriftsartikel (refereegranskat)abstract
- The rate and extent of drug dissolution in the gastrointestinal (GI) tract are highly dependent upon drug physicochemical properties and GI fluid properties. Biorelevant dissolution media (BDM), which aim to facilitate in vitro prediction of in vivo dissolution performance, have evolved with our understanding of GI physiology. However, BDM with a variety of properties and compositions are available, making the choice of dissolution medium challenging. In this tutorial, we describe a simple and quantitative methodology for selecting practical, yet physiologically relevant BDM representative of fasted humans for evaluating dissolution of immediate release formulations. Specifically, this methodology describes selection of pH, buffer species, and concentration and evaluates the importance of including bile salts and phospholipids in the BDM based upon drug substance log D, pK(a), and intrinsic solubility. The methodology is based upon a mechanistic understanding of how three main factors affect dissolution, including (1) drug ionization at gastrointestinal pH, (2) alteration of surface pH by charged drug species, and (3) drug solubilization in mixed lipidic aggregates comprising bile salts and phospholipids. Assessment of this methodology through testing and comparison with literature reports showed that the recommendations correctly identified when a biorelevant buffer capacity or the addition of bile salts and phospholipids to the medium would appreciably change the drug dissolution profile. This methodology can enable informed decisions about when a time, complexity, and/or cost-saving buffer is expected to lead to physiologically meaningful in vitro dissolution testing, versus when a more complex buffer would be required.
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