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.
The angiotensin receptor–neprilysin inhibitor LCZ696 was compared with the ACE inhibitor enalapril in patients with advanced heart failure. LCZ696 was superior to enalapril in all outcomes. ...Neprilysin inhibition may replace ACE inhibition for the treatment of heart failure.
Angiotensin-converting–enzyme (ACE) inhibitors have been the cornerstone of the treatment for heart failure and a reduced ejection fraction for nearly 25 years, since enalapril was shown to reduce the risk of death in two trials.
1
,
2
Long-term treatment with enalapril decreased the relative risk of death by 16% among patients with mild-to-moderate symptoms.
2
The effect of angiotensin-receptor blockers (ARBs) on mortality has been inconsistent,
3
,
4
and thus, these drugs are recommended primarily for patients who have unacceptable side effects (primarily cough) while receiving ACE inhibitors. Subsequent studies showed that the use of beta-blockers and mineralocorticoid-receptor antagonists, when added to ACE . . .
A consequent tendency toward high-performance quantum information processing is to develop the fully integrated photonic chip. Here, we report the on-chip generation and manipulation of entangled ...photons based on reconfigurable lithium-niobate waveguide circuits. By introducing a periodically poled structure into the waveguide circuits, two individual photon-pair sources with a controllable electro-optic phase shift are produced within a Hong-Ou-Mandel interferometer, resulting in a deterministically separated identical photon pair. The state is characterized by 92.9±0.9% visibility Hong-Ou-Mandel interference. The photon flux reaches ∼1.4×10(7) pairs nm-1 mW-1. The whole chip is designed to contain nine similar units to produce identical photon pairs spanning the telecom C and L band by the flexible engineering of nonlinearity. Our work presents a scenario for on-chip engineering of different photon sources and paves the way to fully integrated quantum technologies.
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 paper explores the influence of the confining stress on rock fragmentation under the cutter of tunnel boring machine (TBM) by indentation test. Acoustic emission (AE) system was employed for ...real-time monitoring the rock fragmentation process during the indentation test. Granite and marble samples were used in the indentation test. The rock fragmentation processes with the different confining stress levels was studied based on the characteristics of force–penetration depth curve and the AE parameters, including AE energy rate, hit counts, amplitude and location of AE events. After the indentation test, the rock samples were cut along the centerline of rock samples and subsequently the crack distribution and the size of crushed zone were measured. The test results showed that the force for crack initiation and crushed zone size increased with increasing confining stress. The cracks tend to propagate to the free surface as the confining stress increases. But for the marble samples, there exists a critical confining stress condition, such that if the confining stress is more than the critical value, the force for crack initiation and crushed zone size decrease dramatically. Moreover, it was found that rock slabbing induced by confining stress had occurred before TBM cutter indentation. Such confining stress condition promotes rock fragmentation.
•Influence of confining stress on rock fragmentation by a TBM cutter is studied by indentation test.•AE technique is used for real-time monitoring rock fragmentation during indentation test.•The damage zone and crack distribution are observed by the cross-section of the failed samples.
The angiotensin-receptor-neprilysin inhibitor (ARNI) LCZ696 reduced cardiovascular deaths and all-cause mortality compared with enalapril in patients with chronic heart failure in the prospective ...comparison of ARNI with an Angiotensin-Converting Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) trial. To more completely understand the components of this mortality benefit, we examined the effect of LCZ696 on mode of death.
PARADIGM-HF was a prospective, double-blind, randomized trial in 8399 patients with chronic heart failure, New York Heart Association Class II-IV symptoms, and left ventricular ejection fraction ≤40% receiving guideline-recommended medical therapy and followed for a median of 27 months. Mode of death was adjudicated by a blinded clinical endpoints committee. The majority of deaths were cardiovascular (80.9%), and the risk of cardiovascular death was significantly reduced by treatment with LCZ (hazard ratio, HR 0.80, 95% CI 0.72-0.89, P < 0.001). Among cardiovascular deaths, both sudden cardiac death (HR 0.80, 95% CI 0.68-0.94, P = 0.008) and death due to worsening heart failure (HR 0.79, 95% CI 0.64-0.98, P = 0.034) were reduced by treatment with LCZ696 compared with enalapril. Deaths attributed to other cardiovascular causes, including myocardial infarction and stroke, were infrequent and distributed evenly between treatment groups, as were non-cardiovascular deaths.
LCZ696 was superior to enalapril in reducing both sudden cardiac deaths and deaths from worsening heart failure, which accounted for the majority of cardiovascular deaths.
https://clinicaltrials.gov/, NCT01035255.
This Letter reports a measurement of the flux and energy spectrum of electron antineutrinos from six 2.9 GWth nuclear reactors with six detectors deployed in two near (effective baselines 512 and 561 ...m) and one far (1579 m) underground experimental halls in the Daya Bay experiment. Using 217 days of data, 296 721 and 41 589 inverse β decay (IBD) candidates were detected in the near and far halls, respectively. The measured IBD yield is (1.55±0.04) ×10(-18) cm(2) GW(-1) day(-1) or (5.92±0.14) ×10(-43) cm(2) fission(-1). This flux measurement is consistent with previous short-baseline reactor antineutrino experiments and is 0.946±0.022 (0.991±0.023) relative to the flux predicted with the Huber-Mueller (ILL-Vogel) fissile antineutrino model. The measured IBD positron energy spectrum deviates from both spectral predictions by more than 2σ over the full energy range with a local significance of up to ∼4σ between 4-6 MeV. A reactor antineutrino spectrum of IBD reactions is extracted from the measured positron energy spectrum for model-independent predictions.
High-β_{θe} (a ratio of the electron thermal pressure to the poloidal magnetic pressure) steady-state long-pulse plasmas with steep central electron temperature gradient are achieved in the ...Experimental Advanced Superconducting Tokamak. An intrinsic current is observed to be modulated by turbulence driven by the electron temperature gradient. This turbulent current is generated in the countercurrent direction and can reach a maximum ratio of 25% of the bootstrap current. Gyrokinetic simulations and experimental observations indicate that the turbulence is the electron temperature gradient mode (ETG). The dominant mechanism for the turbulent current generation is due to the divergence of ETG-driven residual flux of current. Good agreement has been found between experiments and theory for the critical value of the electron temperature gradient triggering ETG and for the level of the turbulent current. The maximum values of turbulent current and electron temperature gradient lead to the destabilization of an m/n=1/1 kink mode, which by counteraction reduces the turbulence level (m and n are the poloidal and toroidal mode number, respectively). These observations suggest that the self-regulation system including turbulence, turbulent current, and kink mode is a contributing mechanism for sustaining the steady-state long-pulse high-β_{θe} regime.
Abstract
In its orthorhombic
T
d
polymorph, MoTe
2
is a type-II Weyl semimetal, where the Weyl fermions emerge at the boundary between electron and hole pockets. Non-saturating magnetoresistance and ...superconductivity were also observed in
T
d
-MoTe
2
. Understanding the superconductivity in
T
d
-MoTe
2
, which was proposed to be topologically non-trivial, is of eminent interest. Here, we report high-pressure muon-spin rotation experiments probing the temperature-dependent magnetic penetration depth in
T
d
-MoTe
2
. A substantial increase of the superfluid density and a linear scaling with the superconducting critical temperature
T
c
is observed under pressure. Moreover, the superconducting order parameter in
T
d
-MoTe
2
is determined to have 2-gap
s
-wave symmetry. We also exclude time-reversal symmetry breaking in the superconducting state with zero-field μSR experiments. Considering the strong suppression of
T
c
in MoTe
2
by disorder, we suggest that topologically non-trivial
s
+−
state is more likely to be realized in MoTe
2
than the topologically trivial
s
++
state.
FOXM1 has been implicated in taxane resistance, but the molecular mechanism involved remains elusive. In here, we show that FOXM1 depletion can sensitize breast cancer cells and mouse embryonic ...fibroblasts into entering paclitaxel-induced senescence, with the loss of clonogenic ability, and the induction of senescence-associated β-galactosidase activity and flat cell morphology. We also demonstrate that FOXM1 regulates the expression of the microtubulin-associated kinesin KIF20A at the transcriptional level directly through a Forkhead response element (FHRE) in its promoter. Similar to FOXM1, KIF20A expression is downregulated by paclitaxel in the sensitive MCF-7 breast cancer cells and deregulated in the paclitaxel-resistant MCF-7Tax(R) cells. KIF20A depletion also renders MCF-7 and MCF-7Tax(R) cells more sensitive to paclitaxel-induced cellular senescence. Crucially, resembling paclitaxel treatment, silencing of FOXM1 and KIF20A similarly promotes abnormal mitotic spindle morphology and chromosome alignment, which have been shown to induce mitotic catastrophe-dependent senescence. The physiological relevance of the regulation of KIF20A by FOXM1 is further highlighted by the strong and significant correlations between FOXM1 and KIF20A expression in breast cancer patient samples. Statistical analysis reveals that both FOXM1 and KIF20A protein and mRNA expression significantly associates with poor survival, consistent with a role of FOXM1 and KIF20A in paclitaxel action and resistance. Collectively, our findings suggest that paclitaxel targets the FOXM1-KIF20A axis to drive abnormal mitotic spindle formation and mitotic catastrophe and that deregulated FOXM1 and KIF20A expression may confer paclitaxel resistance. These findings provide insights into the underlying mechanisms of paclitaxel resistance and have implications for the development of predictive biomarkers and novel chemotherapeutic strategies for paclitaxel resistance.