Codeine is bioactivated to morphine, a strong opioid agonist, by the hepatic cytochrome P450 2D6 (CYP2D6); hence, the efficacy and safety of codeine as an analgesic are governed by CYP2D6 ...polymorphisms. Codeine has little therapeutic effect in patients who are CYP2D6 poor metabolizers, whereas the risk of morphine toxicity is higher in ultrarapid metabolizers. The purpose of this guideline (periodically updated at http://www.pharmgkb.org) is to provide information relating to the interpretation of CYP2D6 genotype test results to guide the dosing of codeine.
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Codeine is bioactivated to morphine, a strong opioid agonist, by the hepatic cytochrome P450 2D6 (CYP2D6); hence, the efficacy and safety of codeine are governed by CYP2D6 activity. Polymorphisms are ...a major cause of CYP2D6 variability. We summarize evidence from the literature supporting this association and provide therapeutic recommendations for codeine based on CYP2D6 genotype. This document is an update to the 2012 Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for CYP2D6 genotype and codeine therapy.
Clinical Pharmacology & Therapeutics (2014); 95 4, 376–382. doi:10.1038/clpt.2013.254
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Our study aims to enhance process understanding of the long-term (decadal and longer) cyclic marsh dynamics by identifying the mechanisms that translate large-scale physical forcing in the system ...into vegetation change, in particular (i) the initiation of lateral erosion on an expanding marsh, and (ii) the control of seedling establishment in front of an eroding marsh-cliff. Short-term sediment dynamics (i.e., seasonal and shorter changes in sediment elevation) at the mudflat causes variation in mudflat elevation over time (δZTF). The resulting difference in elevation between the tidal flat and adjacent marsh (ΔZ) initiates lateral marsh erosion. Marsh erosion rate was found to depend on sediment type and to increase with increasing ΔZ and hydrodynamic exposure. Laboratory and field experiments revealed that seedling establishment was negatively impacted by an increasing δZTF. As the amplitude of δZTF increases towards the channel, expanding marshes become more prone to lateral erosion the further they extend on a tidal flat, and the chance for seedlings to establish increases with the distance that marsh has eroded back towards the land. This processbased understanding, showing the role of sediment dynamics as explanatory factor for marsh cyclicity, is important for protecting and restoring valuable marsh ecosystems. Overall, our experiments emphasize the need for understanding the connections between neighbouring ecosystems such as mudflat and salt marsh.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NMLJ, NUK, OILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK
The Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines for HLA‐B*58:01 Genotype and Allopurinol Dosing was originally published in February 2013. We reviewed the recent literature ...and concluded that none of the evidence would change the therapeutic recommendations in the original guideline; therefore, the original publication remains clinically current. However, we have updated the Supplemental Material and included additional resources for applying CPIC guidelines into the electronic health record. Up‐to‐date information can be found at PharmGKB (http://www.pharmgkb.org).
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Phenytoin is a widely used antiepileptic drug with a narrow therapeutic index and large interpatient variability, partly due to genetic variations in the gene encoding cytochrome P450 (CYP)2C9 ...(CYP2C9). Furthermore, the variant allele HLA‐B*15:02, encoding human leukocyte antigen, is associated with an increased risk of Stevens–Johnson syndrome and toxic epidermal necrolysis in response to phenytoin treatment. We summarize evidence from the published literature supporting these associations and provide recommendations for the use of phenytoin based on CYP2C9 and/or HLA‐B genotype (also available on PharmGKB: http://www.pharmgkb.org). The purpose of this guideline is to provide information for the interpretation of HLA‐B and/or CYP2C9 genotype tests so that the results can guide dosing and/or use of phenytoin. Detailed guidelines for the use of phenytoin as well as analyses of cost‐effectiveness are out of scope. Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines are periodically updated at http://www.pharmgkb.org.
Clinical Pharmacology & Therapeutics (2014); 96 5, 542–548. doi:10.1038/clpt.2014.159
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Allopurinol is the most commonly used drug for the treatment of hyperuricemia and gout. However, allopurinol is also one of the most common causes of severe cutaneous adverse reactions (SCARs), which ...include drug hypersensitivity syndrome, Stevens–Johnson syndrome, and toxic epidermal necrolysis. A variant allele of the human leukocyte antigen (HLA)‐B, HLA‐B*58:01, associates strongly with allopurinol‐induced SCAR. We have summarized the evidence from the published literature and developed peer‐reviewed guidelines for allopurinol use based on HLA‐B genotype.
Clinical Pharmacology & Therapeutics (2013); 93 2, 153–158. doi:10.1038/clpt.2012.209
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Current regulatory guidances do not address specific study designs for in vitro and in vivo drug-drug interaction studies. There is a common desire by regulatory authorities and by industry sponsors ...to harmonize approaches, to allow for a better assessment of the significance of findings across different studies and drugs. There is also a growing consensus for the standardization of cytochrome P450 (P450) probe substrates, inhibitors and inducers and for the development of classification systems to improve the communication of risk to health care providers and to patients. While existing guidances cover mainly P450-mediated drug interactions, the importance of other mechanisms, such as transporters, has been recognized more recently, and should also be addressed. This article was prepared by the Pharmaceutical Research and Manufacturers of America (PhRMA) Drug Metabolism and Clinical Pharmacology Technical Working Groups and represents the current industry position. The intent is to define a minimal best practice for in vitro and in vivo pharmacokinetic drug-drug interaction studies targeted to development (not discovery support) and to define a data package that can be expected by regulatory agencies in compound registration dossiers.
It is the purpose of this paper to provide a comprehensive documentation of the new NCAR (National Center for Atmospheric Research) version of the spectral element (SE) dynamical core as part of the ...Community Earth System Model (CESM2.0) release. This version differs from previous releases of the SE dynamical core in several ways. Most notably the hybrid sigma vertical coordinate is based on dry air mass, the condensates are dynamically active in the thermodynamic and momentum equations (also referred to as condensate loading), and the continuous equations of motion conserve a more comprehensive total energy that includes condensates. Not related to the vertical coordinate change, the hyperviscosity operators and the vertical remapping algorithms have been modified. The code base has been significantly reduced, sped up, and cleaned up as part of integrating SE as a dynamical core in the CAM (Community Atmosphere Model) repository rather than importing the SE dynamical core from High‐Order Methods Modeling environment as an external code.
Key Points
The CESM2.0 release of the spectral element dynamical core (CAM‐SE) is documented
Model has comprehensive treatment of condensates and energy
The CAM‐SE model has been sped up significantly compared to its predecessor CAM‐HOMME
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Summary
Desulfatibacillum alkenivorans AK‐01 serves as a model organism for anaerobic alkane biodegradation because of its distinctive biochemistry and metabolic versatility. The D. alkenivorans ...genome provides a blueprint for understanding the genetic systems involved in alkane metabolism including substrate activation, CoA ligation, carbon‐skeleton rearrangement and decarboxylation. Genomic analysis suggested a route to regenerate the fumarate needed for alkane activation via methylmalonyl‐CoA and predicted the capability for syntrophic alkane metabolism, which was experimentally verified. Pathways involved in the oxidation of alkanes, alcohols, organic acids and n‐saturated fatty acids coupled to sulfate reduction and the ability to grow chemolithoautotrophically were predicted. A complement of genes for motility and oxygen detoxification suggests that D. alkenivorans may be physiologically adapted to a wide range of environmental conditions. The D. alkenivorans genome serves as a platform for further study of anaerobic, hydrocarbon‐oxidizing microorganisms and their roles in bioremediation, energy recovery and global carbon cycling.
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To unravel the relation between hydrodynamic forcing and the dynamics of the tidal flat–salt-marsh ecosystem, we compared hydrodynamic forcing in terms of proxies relevant to bed sediment motion for ...four tidal flat–salt-marsh ecosystems that were contrasting in terms of wind exposure (sheltered vs. exposed) and lateral development (shrinking vs. expanding). Wave and current field measurements on these four contrasting tidal flat and salt-marsh ecosystems indicated that the hydrodynamic forcing on the bottom sediment (bed shear stress) was strongly influenced by wind-generated waves, more so than by tidal- or wind-drive currents. The measurements further showed that the hydrodynamic forcing decreased considerably landward of the marsh cliff, highlighting a transition from vigorous (tidal flat and pioneer zone) to sluggish (mature marsh) fluid forcing. Spatial wave modeling using measured wind, revealed that the time-integrated wave forcing on the intertidal mudflat in front of the marsh (i.e., the potential bed sediment pickup) was a factor two higher for salt marshes that are laterally shrinking than for laterally expanding marshes, regardless of whether these marshes were exposed to or sheltered from the wind. The same result could not be obtained from a straightforward wind speed and fetch length approach for estimating wave forcing. This confirmed that wave force estimates required spatial modeling to be consistent with the sites trends of shrinking or expanding marshes and wind exposure is not enough to characterize the wave forcing at these sites.
Seasonal changes in wave forcing identified from wind measurements potentially provide an alternative mechanism for marsh cliff formation. During the calm summer, fine sediments switches from the water column to the bed. During the following winter, fine sediment is retained within the vegetated regions while being returned to the water column from the bare tidal flats. The continuous slow upward growth of vegetated areas combined with the seasonal cyclic tidal flat elevations, could, during winter, cause a discontinuity at the bare/vegetated boundary. If this discontinuity grows large enough for plant die-off to occur, then a small cliff will form.
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