This document is an update to the 2011 Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for CYP2C9 and VKORC1 genotypes and warfarin dosing. Evidence from the published literature ...is presented for CYP2C9, VKORC1, CYP4F2, and rs12777823 genotype‐guided warfarin dosing to achieve a target international normalized ratio of 2–3 when clinical genotype results are available. In addition, this updated guideline incorporates recommendations for adult and pediatric patients that are specific to continental ancestry.
Warfarin is a widely used anticoagulant with a narrow therapeutic index and large interpatient variability in the dose required to achieve target anticoagulation. Common genetic variants in the ...cytochrome P450–2C9 (CYP2C9) and vitamin K–epoxide reductase complex (VKORC1) enzymes, in addition to known nongenetic factors, account for ~50% of warfarin dose variability. The purpose of this article is to assist in the interpretation and use of CYP2C9 and VKORC1 genotype data for estimating therapeutic warfarin dose to achieve an INR of 2–3, should genotype results be available to the clinician. The Clinical Pharmacogenetics Implementation Consortium (CPIC) of the National Institutes of Health Pharmacogenomics Research Network develops peer–reviewed gene–drug guidelines that are published and updated periodically on http://www.pharmgkb.org based on new developments in the field.1
Clinical Pharmacology & Therapeutics (2011) 90 4, 625–629. doi:10.1038/clpt.2011.185
There is substantial variation in the dose of warfarin required to achieve therapeutic anticoagulation. In this study, mathematical models for warfarin dosage were constructed that used either ...clinical factors alone or clinical and genetic factors. The model incorporating genetic factors, when tested retrospectively with data from an international cohort, provided better estimates than a model that included only clinical factors.
Mathematical models for warfarin dosage were constructed that used either clinical factors alone or clinical and genetic factors. The model incorporating genetic factors provided better estimates than a model that included only clinical factors.
Warfarin is the most widely used oral anticoagulant agent worldwide; more than 30 million prescriptions were written for this drug in the United States in 2004.
1
The appropriate dose of warfarin is difficult to establish because it can vary by a factor of 10 among patients, and the consequences of taking an incorrect dose can be catastrophic. Because incorrect doses contribute to a high rate of adverse effects, there is interest in developing improved strategies for determining the appropriate dose.
2
Clinical factors, demographic variables, and variations in two genes — cytochrome P450, family 2, subfamily C, polypeptide 9 (
CYP2C9
. . .
The Boston University-Five College Radio Astronomy Observatory Galactic Ring Survey is a new survey of Galactic super(13)CO J = 1 1 0 emission. The survey used the SEQUOIA multipixel array on the ...Five College Radio Astronomy Observatory 14m telescope to cover a longitude range of l = 18-55.7 and a latitude range of |b| < 1, a total of 75.4 deg super(2). Using both position-switching and On-The-Fly mapping modes, we achieved an angular sampling of 22, better than half of the telescope's 46 angular resolution. The survey's velocity coverage is -5 to 135 km s super(-1) for Galactic longitudes l, 40 and -5 to 85 km s super(-1) for Galactic longitudes l > 40. At the velocity resolution of 0.21 km s super(-1), the typical rms sensitivity is s(T super(*)A) 6 0.13 K. The survey comprises a total of 1,993,522 spectra. We show integrated intensity images (zeroth moment maps), channel maps, position-velocity diagrams, and an average spectrum of the completed survey data set. We also discuss the telescope and instrumental parameters, the observing modes, the data reduction processes, and the emission and noise characteristics of the data set. The Galactic Ring Survey data are available to the community online or in DVD form by request.
Aim
To determine whether using HbA1c for screening and management could be confounded by age differences, whether age effects can be explained by unrecognized diabetes and prediabetes, insulin ...resistance or postprandial hyperglycaemia, and whether the effects of aging have an impact on diagnostic accuracy.
Methods
We conducted a cross‐sectional analysis in adults without known diabetes in the Screening for Impaired Glucose Tolerance (SIGT) study 2005–2008 (n=1573) and the National Health and Nutrition Examination Survey (NHANES) 2005–2006 (n=1184).
Results
Both glucose intolerance and HbA1c levels increased with age. In univariate analyses including all subjects, HbA1c levels increased by 0.93 mmol/mol (0.085%) per 10 years of age in the SIGT study and by 1.03 mmol/mol (0.094%) per 10 years in the NHANES; in both datasets, the HbA1c increase was 0.87 mmol/mol (0.08%) per 10 years in subjects without diabetes, and 0.76 mmol/mol (0.07%) per 10 years in subjects with normal glucose tolerance, all P<0.001. In multivariate analyses of subjects with normal glucose tolerance, the relationship between age and HbA1c remained significant (P<0.001) after adjustment for covariates including race, BMI, waist circumference, sagittal abdominal diameter, triglyceride/HDL ratio, and fasting and 2‐h plasma glucose and other glucose levels, as assessed by an oral glucose tolerance test. In both datasets, the HbA1c of an 80‐year‐old individual with normal glucose tolerance would be 3.82 mmol/mol (0.35%) greater than that of a 30‐year‐old with normal glucose tolerance, a difference that is clinically significant. Moreover, the specificity of HbA1c‐based diagnostic criteria for prediabetes decreased substantially with increasing age (P<0.0001).
Conclusions
In two large datasets, using different methods to measure HbA1c, the association of age with higher HbA1c levels: was consistent and similar; was both statistically and clinically significant; was unexplained by features of aging; and reduced diagnostic specificity. Age should be taken into consideration when using HbA1c for the diagnosis and management of diabetes and prediabetes.
What's new?
Measures of HbA1c are used for screening and management, but HbA1c levels rise with increasing age.
Higher HbA1c levels with increasing age cannot be attributed to unrecognized diabetes or prediabetes, postprandial hyperglycaemia or insulin resistance.
Differences in HbA1c levels with age are substantial: levels are 3.82 mmol/mol (0.35%) greater for an 80‐year‐old than for a 30‐year‐old individual, with the same glucose levels.
The specificity of HbA1c‐based criteria for prediabetes decreases with increasing age.
Screening with HbA1c will tend to overdiagnose diabetes and prediabetes in older patients.
Guiding management based only on HbA1c levels might increase hypoglycaemia in older patients.
Practitioners should monitor glucose as well as HbA1c levels.
Data from large‐scale debris‐flow experiments are combined with modeling of particle‐size segregation to explain the formation of lateral levees enriched in coarse grains. The experimental flows ...consisted of 10 m3 of water‐saturated sand and gravel, which traveled ∼80 m down a steeply inclined flume before forming an elongated leveed deposit 10 m long on a nearly horizontal runout surface. We measured the surface velocity field and observed the sequence of deposition by seeding tracers onto the flow surface and tracking them in video footage. Levees formed by progressive downslope accretion approximately 3.5 m behind the flow front, which advanced steadily at ∼2 m s−1 during most of the runout. Segregation was measured by placing ∼600 coarse tracer pebbles on the bed, which, when entrained into the flow, segregated upwards at ∼6–7.5 cm s−1. When excavated from the deposit these were distributed in a horseshoe‐shaped pattern that became increasingly elevated closer to the deposit termination. Although there was clear evidence for inverse grading during the flow, transect sampling revealed that the resulting leveed deposit was strongly graded laterally, with only weak vertical grading. We construct an empirical, three‐dimensional velocity field resembling the experimental observations, and use this with a particle‐size segregation model to predict the segregation and transport of material through the flow. We infer that coarse material segregates to the flow surface and is transported to the flow front by shear. Within the flow head, coarse material is overridden, then recirculates in spiral trajectories due to size‐segregation, before being advected to the flow edges and deposited to form coarse‐particle‐enriched levees.
Key Points
Coarse particle levees form in debris flows by progressive streamwise accretion
Coarse grains are transported to the flow front, then laterally into the levees
Grain size segregation profoundly affects flow dynamics and deposit structure
Robust establishment of survival in multiple myeloma (MM) and its relationship to recurrent genetic aberrations is required as outcomes are variable despite apparent similar staging. We assayed copy ...number alterations (CNA) and translocations in 1036 patients from the NCRI Myeloma XI trial and linked these to overall survival (OS) and progression-free survival. Through a meta-anlysis of these data with data from MRC Myeloma IX trial, totalling 1905 newly diagnosed MM patients (NDMM), we confirm the association of t(4;14), t(14;16), t(14;20), del(17p) and gain(1q21) with poor prognosis with hazard ratios (HRs) for OS of 1.60 (P=4.77 × 10
), 1.74 (P=0.0005), 1.90 (P=0.0089), 2.10 (P=8.86 × 10
) and 1.68 (P=2.18 × 10
), respectively. Patients with 'double-hit' defined by co-occurrence of at least two adverse lesions have an especially poor prognosis with HRs for OS of 2.67 (P=8.13 × 10
) for all patients and 3.19 (P=1.23 × 10
) for intensively treated patients. Using comprehensive CNA and translocation profiling in Myeloma XI we also demonstrate a strong association between t(4;14) and BIRC2/BIRC3 deletion (P=8.7 × 10
), including homozygous deletion. Finally, we define distinct sub-groups of hyperdiploid MM, with either gain(1q21) and CCND2 overexpression (P<0.0001) or gain(11q25) and CCND1 overexpression (P<0.0001). Profiling multiple genetic lesions can identify MM patients likely to relapse early allowing stratification of treatment.
Essentials
High‐quality data are lacking on use of prophylaxis in adults with hemophilia and arthropathy.
SPINART was a 3‐year randomized clinical trial of late/tertiary prophylaxis vs on‐demand ...therapy.
Prophylaxis improved function, quality of life, activity and pain but not joint structure by MRI.
Prophylaxis improves function but must start before joint bleeding onset to prevent arthropathy.
Summary
Background
Limited data exist on the impact of prophylaxis on adults with severe hemophilia A and pre‐existing joint disease.
Objectives
To describe 3‐year bleeding, joint health and structure, health‐related quality‐of‐life (HRQoL) and other outcomes from the open‐label, randomized, multinational SPINART study.
Patients/Methods
Males aged 12–50 years with severe hemophilia A, ≥ 150 factor VIII exposure days, no inhibitors and no prophylaxis for > 12 consecutive months in the past 5 years were randomized to sucrose‐formulated recombinant FVIII prophylaxis or on‐demand therapy (OD). Data collected included total and joint bleeding events (BEs), joint structure (magnetic resonance imaging MRI), joint health (Colorado Adult Joint Assessment Scale CAJAS), HRQoL, pain, healthcare resource utilization (HRU), activity, and treatment satisfaction.
Results
Following 3 years of prophylaxis, adults maintained excellent adherence, with a 94% reduction in BEs despite severe pre‐existing arthropathy; 35.7% and 76.2% of prophylaxis participants were bleed‐free or had fewer than two BEs per year, respectively. As compared with OD, prophylaxis was associated with improved CAJAS scores (least squares LS mean, − 0.31 n = 42 versus + 0.63 n = 42) and HAEMO‐QoL‐A scores (LS mean, + 3.98 n = 41 versus − 6.00 n = 42), less chronic pain (50% decrease), and approximately two‐fold less HRU; activity, Euro QoL‐5D‐3L (EQ‐5D‐3L) scores and satisfaction scores also favored prophylaxis. However, MRI score changes were not different for prophylaxis versus OD (LS mean, + 0.79 n = 41 versus + 0.96 n = 38).
Conclusions
Over a period of 3 years, prophylaxis versus OD in adults with severe hemophilia A and arthropathy led to decreased bleeding, pain, and HRU, better joint health, activity, satisfaction, and HRQoL, but no reduction in structural arthropathy progression, suggesting that pre‐existing joint arthropathy may be irreversible.
Focusing on the roles of Russian Orthodoxy and Islam in constituting, challenging and changing national and ethnic identities in Russia, this study takes Tsarist and Soviet legacies into account, ...paying special attention to the evolution of the relationship between religious teachings and political institutions through the late 19th and 20th centuries. The volume explicitly discusses and compares the role of Russia's two major religions, Orthodoxy and Islam, in forging identity in the modern era and brings an innovative blend of sociological, historical, linguistic and geographic scholarship to the problem of post-Soviet Russian identity. This comprehensive volume is suitable for courses on post-Soviet politics, Russian studies, religion and political culture.
Contents: Religion after Communism: belief, identity, and the Soviet legacy in Russia, Juliet Johnson; Ethno-religious identity in modern Russia: orthodoxy and Islam compared, Marietta Stepaniants; Orthodoxy, ethnicity, and mass Ethnophobias in the late Tsarist era, Liudmila Gatagova; In search of the "Russian Idea": a view from inside the Russian Orthodox church, Father Georgii Chistiakov; Tolerance and extremism: Russian ethnicity in the Orthodox discourse of the 1990s, Svetlana Ryzhova; Islam and the emergence of Tatar National identity, Aidar Yuzeev; Islam and the construction of Tatar sociolinguistic identity, Suzanne Wertheim; The Ponticization of Ethnic religious identity in Dagestan, Zagir Arukhov; Modern identities in Russia: a new struggle for the soul?, Juliet Johnson; Index.
Juliet Johnson is Associate Professor of Political Science at McGill University, Canada. She has published on topics ranging from post-communist political economy to the politics of Russian national identity formation. Marietta Stepaniants is affiliated with the Institute of Philosophy of the Russian Academy of Sciences as well as the State University of the Humanities (Moscow). Over her distinguished career, she has published numerous books and scholarly articles. Benjamin Forest is Associate Professor of Geography at Dartmouth College, USA. He has published articles on identity, race and ethnicity, and political representation.
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