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
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.
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
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
. . .
Anatomy of STEM teaching in North American universities Stains, M; Harshman, J; Barker, M K ...
Science (American Association for the Advancement of Science),
2018-Mar-30, 2018-03-30, 20180330, Letnik:
359, Številka:
6383
Journal Article
Recenzirano
Odprti dostop
Lecture is prominent, but practices vary
A large body of evidence demonstrates that strategies that promote student interactions and cognitively engage students with content (
1
) lead to gains in ...learning and attitudinal outcomes for students in science, technology, engineering, and mathematics (STEM) courses (
1
,
2
). Many educational and governmental bodies have called for and supported adoption of these student-centered strategies throughout the undergraduate STEM curriculum. But to the extent that we have pictures of the STEM undergraduate instructional landscape, it has mostly been provided through self-report surveys of faculty members, within a particular STEM discipline e.g., (
3
–
6
). Such surveys are prone to reliability threats and can underestimate the complexity of classroom environments, and few are implemented nationally to provide valid and reliable data (
7
). Reflecting the limited state of these data, a report from the U.S. National Academies of Sciences, Engineering, and Medicine called for improved data collection to understand the use of evidence-based instructional practices (
8
). We report here a major step toward a characterization of STEM teaching practices in North American universities based on classroom observations from over 2000 classes taught by more than 500 STEM faculty members across 25 institutions.
If strong electron-electron interactions between neighboring Fe atoms mediate the Cooper pairing in iron-pnictide superconductors, then specific and distinct anisotropic superconducting energy gaps Δ ...j (K⃗) should appear on the different electronic bands i. Here, we introduce intraband Bogoliubov quasiparticle scattering interference (QPI) techniques for determination of Δ j (K⃗) in such materials, focusing on lithium iron arsenide (LiFeAs). We identify the three hole-like bands assigned previously as γ, α₂ and αⁱ, and we determine the anisotropy, magnitude, and relative orientations of their Δ j (K⃗). These measurements will advance quantitative theoretical analysis of the mechanism of Cooper pairing in iron-based superconductivity.
There is a need to increase access to surgical treatments in African countries, but perioperative complications represent a major global health-care burden. There are few studies describing surgical ...outcomes in Africa.
We did a 7-day, international, prospective, observational cohort study of patients aged 18 years and older undergoing any inpatient surgery in 25 countries in Africa (the African Surgical Outcomes Study). We aimed to recruit as many hospitals as possible using a convenience sampling survey, and required data from at least ten hospitals per country (or half the surgical centres if there were fewer than ten hospitals) and data for at least 90% of eligible patients from each site. Each country selected one recruitment week between February and May, 2016. The primary outcome was in-hospital postoperative complications, assessed according to predefined criteria and graded as mild, moderate, or severe. Data were presented as median (IQR), mean (SD), or n (%), and compared using t tests. This study is registered on the South African National Health Research Database (KZ_2015RP7_22) and ClinicalTrials.gov (NCT03044899).
We recruited 11 422 patients (median 29 IQR 10–70) from 247 hospitals during the national cohort weeks. Hospitals served a median population of 810 000 people (IQR 200 000–2 000 000), with a combined number of specialist surgeons, obstetricians, and anaesthetists totalling 0·7 (0·2–1·9) per 100 000 population. Hospitals did a median of 212 (IQR 65–578) surgical procedures per 100 000 population each year. Patients were younger (mean age 38·5 years SD 16·1), with a lower risk profile (American Society of Anesthesiologists median score 1 IQR 1–2) than reported in high-income countries. 1253 (11%) patients were infected with HIV, 6504 procedures (57%) were urgent or emergent, and the most common procedure was caesarean delivery (3792 patients, 33%). Postoperative complications occurred in 1977 (18·2%, 95% CI 17·4–18·9) of 10 885 patients. 239 (2·1%) of 11 193 patients died, 225 (94·1%) after the day of surgery. Infection was the most common complication (1156 10·2% of 10 970 patients), of whom 112 (9·7%) died.
Despite a low-risk profile and few postoperative complications, patients in Africa were twice as likely to die after surgery when compared with the global average for postoperative deaths. Initiatives to increase access to surgical treatments in Africa therefore should be coupled with improved surveillance for deteriorating physiology in patients who develop postoperative complications, and the resources necessary to achieve this objective.
Medical Research Council of South Africa.
The effect of anthropogenic aerosols on cloud droplet concentrations and radiative properties is the source of one of the largest uncertainties in the radiative forcing of climate over the industrial ...period. This uncertainty affects our ability to estimate how sensitive the climate is to greenhouse gas emissions. Here we perform a sensitivity analysis on a global model to quantify the uncertainty in cloud radiative forcing over the industrial period caused by uncertainties in aerosol emissions and processes. Our results show that 45 per cent of the variance of aerosol forcing since about 1750 arises from uncertainties in natural emissions of volcanic sulphur dioxide, marine dimethylsulphide, biogenic volatile organic carbon, biomass burning and sea spray. Only 34 per cent of the variance is associated with anthropogenic emissions. The results point to the importance of understanding pristine pre-industrial-like environments, with natural aerosols only, and suggest that improved measurements and evaluation of simulated aerosols in polluted present-day conditions will not necessarily result in commensurate reductions in the uncertainty of forcing estimates.
Dysregulation of receptor tyrosine kinase MET by various mechanisms occurs in 3%–4% of non-small-cell lung cancer (NSCLC) and is associated with unfavorable prognosis. While MET is a validated drug ...target in lung cancer, the best biomarker strategy for the enrichment of a susceptible patient population still remains to be defined. Towards this end we analyze here primary data from a phase I dose expansion study of the MET inhibitor capmatinib in patients with advanced MET-dysregulated NSCLC.
Eligible patients ≥18 years; Eastern Cooperative Oncology Group (ECOG) performance status ≤2 with MET-dysregulated advanced NSCLC, defined as either (i) MET status by immunohistochemistry (MET IHC) 2+ or 3+ or H-score ≥150, or MET/centromere ratio ≥2.0 or gene copy number (GCN) ≥5, or (ii) epidermal growth factor receptor wild-type (EGFRwt) and centrally assessed MET IHC 3+, received capmatinib at the recommended dose of 400 mg (tablets) or 600 mg (capsules) b.i.d. The primary objective was to determine safety and tolerability; the key secondary objective was to explore antitumor activity. The exploratory end point was the correlation of clinical activity with different biomarker formats.
Of 55 patients with advanced MET-dysregulated NSCLC, 40/55 (73%) had received two or more prior systemic therapies. All patients discontinued treatment, primarily due to disease progression (69.1%). The median treatment duration was 10.4 weeks. The overall response rate per RECIST was 20% (95% confidence interval, 10.4–33.0). In patients with MET GCN ≥6 (n = 15), the overall response rate by both the investigator and central assessments was 47%. The median progression-free survival per investigator for patients with MET GCN ≥6 was 9.3 months (95% confidence interval, 3.8–11.9). Tumor responses were observed in all four patients with METex14. The most common toxicities were nausea (42%), peripheral edema (33%), and vomiting (31%).
MET GCN ≥6 and/or METex14 are suited to predict clinical activity of capmatinib in patients with NSCLC (NCT01324479).
•This study provides first evidence of clinically meaningful antitumor activity of capmatinib in MET-dysregulated NSCLC.•Accurate biomarker selection of the patients is needed to identify the patients expected to respond better to capmatinib.•MET amplification GCN ≥6 and/or METex14 skipping are strong predictive biomarkers for response to capmatinib.•Overexpression alone cannot be considered as a reliable biomarker to predict the efficacy of capmatinib.•Capmatinib is well tolerated with the majority of the AEs grade 1 and 2.
We conducted co-clinical trials in patient-derived xenograft (PDX) models to identify predictive biomarkers for the multikinase inhibitor dovitinib in lung squamous cell carcinoma (LSCC).
The ...PDX01-02 were established from LSCC patients enrolled in the phase II trial of dovitinib (NCT01861197) and PDX03-05 were established from LSCC patients receiving surgery. These five PDX tumors were subjected toin vivo test of dovitinib efficacy, whole exome sequencing and gene expression profiling.
The PDX tumors recapitulate histopathological properties and maintain genomic characteristics of originating tumors. Concordant with clinical outcomes of the trial enrolled-LSCC patients, dovitinib produced substantial tumor regression in PDX-01 and PDX-05, whereas it resulted in tumor progression in PDX-02. PDX-03 and -04 also displayed poor antitumor efficacy to dovitinib. Mutational and genome-wide copy number profiles revealed no correlation between genomic alterations ofFGFR1-3 and sensitivity to dovitinib. Of note, gene expression profiles revealed differentially expressed genes including FGF3 and FGF19 between PDX-01 and 05 and PDX-02-04. Pathway analysis identified two FGFR signaling-related gene sets, FGFR ligand binding/activation and SHC-mediated cascade pathway were substantially up-regulated in PDX-01 and 05, compared with PDX-02-04. The comparison of gene expression profiles between dovitinib-sensitive versus -resistant lung cancer cell lines in the Cancer Cell Line Encyclopedia database also found that transcriptional activation of 18 key signaling components in FGFR pathways can predict the sensitivity to dovitinib both in cell lines and PDX tumors. These results highlight FGFR pathway activation as a key molecular determinant for sensitivity to dovitinib.
FGFR gene expression signatures are predictors for the response to dovitinib in LSCC.
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