Key aspects of statin intolerance leading to treatment discontinuation: a patient perspective

Abstract Background and aims Statins are the standard of care for patients with dyslipidemia, but some patients develop intolerance to treatment. The experience of statin intolerant (SI) patients is poorly understood. The objective of this study was to identify key aspects of SI that may be associated with treatment discontinuation. Methods Using a previously created questionnaire, we conducted a pilot cross-sectional survey to identify items important for describing patient-centric aspects of SI. The study recruited adult (18+) patients with a history of statin-associated side effects from 9 clinics in 6 countries (France, Italy, Norway, Spain, Sweden, and the United Kingdom), who had received statin treatment within the previous two years. Results We surveyed 104 patients (mean age 61.5 SD=11.2 years, 63.5% men, 50% currently on statins). Patients most frequently reported muscle-related symptoms: pain (90.9%), cramps (63.7%), and stiffness (58.2%). Using a 0–10 point scale, significant differences were found between those continuing versus discontinuing their statins for being bothered by side effects (7.5 vs 9.2, p=0.001), for an inability to tolerate side effects (6.7 vs 9.0, p<0.001), and those having too much side effects interference with their daily life (5.7 vs 8.6, p<0.001; see figure). For patients whose doctors worked on adjusting statin regimen, 67% stayed on treatment; for those whose doctors did not, only 10% continued treatment. Conclusions Results of this pilot survey suggest patients who experience greater side effects severity and interference with daily activity, along with lower efforts by clinicians to work with adjusting their statin regimen, are at greater risk for discontinuing treatment. A wider survey and larger study population is needed to confirm the results of this pilot study. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): This study was sponsored by Amgen Inc

Double-flow focused liquid injector for efficient serial femtosecond crystallography

Serial femtosecond crystallography requires reliable and efficient delivery of fresh crystals across the beam of an X-ray free-electron laser over the course of an experiment. We introduce a double-flow focusing nozzle to meet this challenge, with significantly reduced sample consumption, while improving jet stability over previous generations of nozzles. We demonstrate its use to determine the first room-temperature structure of RNA polymerase II at high resolution, revealing new structural details. Moreover, the double flow- focusing nozzles were successfully tested with three other protein samples and the first room temperature structure of an extradiol ring-cleaving dioxygenase was solved by utilizing the improved operation and characteristics of these devices

Testing for hereditary thrombophilia: a retrospective analysis of testing referred to a national laboratory

<p>Abstract</p> <p>Background</p> <p>Predisposition to venous thrombosis may be assessed through testing for defects and/or deficiencies of a number of hereditary factors. There is potential for confusion about which of these tests are appropriate in which settings. At least one set of recommendations has been published to guide such testing, but it is unclear how widely these have been disseminated.</p> <p>Methods</p> <p>We performed a retrospective analysis of laboratory orders and results at a national referral laboratory to gain insight into physicians' ordering practices, specifically comparing them against the ordering practices recommended by a 2002 College of American Pathologists (CAP) consensus conference on thrombophilia testing. Measurements included absolute and relative ordering volumes and positivity rates from approximately 200,000 thrombophilia tests performed from September 2005 through August 2006 at a national reference laboratory. Quality control data were used to estimate the proportion of samples that may have been affected by anticoagulant therapy. A sample of ordering laboratories was surveyed in order to assess potential measurement bias.</p> <p>Results</p> <p>Total antigen assays for protein C, protein S and antithrombin were ordered almost as frequently as functional assays for these analytes. The DNA test for factor V Leiden was ordered much more often than the corresponding functional assay. In addition, relative positivity rates coupled with elevations in prothrombin time (PT) in many of these patients suggest that these tests are often ordered in the setting of oral anticoagulant therapy.</p> <p>Conclusion</p> <p>In this real-world setting, testing for inherited thrombophilia is frequently at odds with the recommendations of the CAP consensus conference. There is a need for wider dissemination of concise thrombophilia testing guidelines.</p

Regulated Expansion of Electricity Transmission Networks: The Effects of Fluctuating Demand and Wind Generation

We study the performance of different regulatory approaches for the expansion of electricity transmission networks in the light of realistic demand patterns and fluctuating wind power. In particular, we are interested in the relative performance of a combined merchant-regulatory mechanism compared to a cost-based and a merchant-like approach. In contrast to earlier research, we explicitly include both an hourly time resolution and fluctuating wind power, which allows representing demand in a very realistic way. This substantially increases the real-world applicability of results compared to previous analyses, which were based on simplifying assumptions. We show that a combined merchant-regulatory regulation, which draws on a cap over the two-part tariff of the Transco, leads to welfare outcomes far superior to the modeled alternatives. This result proves to be robust over a range of different cases and sensitivity analyses. We also find that the intertemporal rebalancing of the two-part tariff carried out by the Transco so as to expand the network is such that the fixed tariff part turns out to be relatively large compared to extension costs

Cross-Modal Object Recognition Is Viewpoint-Independent

BACKGROUND: Previous research suggests that visual and haptic object recognition are viewpoint-dependent both within- and cross-modally. However, this conclusion may not be generally valid as it was reached using objects oriented along their extended y-axis, resulting in differential surface processing in vision and touch. In the present study, we removed this differential by presenting objects along the z-axis, thus making all object surfaces more equally available to vision and touch. METHODOLOGY/PRINCIPAL FINDINGS: Participants studied previously unfamiliar objects, in groups of four, using either vision or touch. Subsequently, they performed a four-alternative forced-choice object identification task with the studied objects presented in both unrotated and rotated (180 degrees about the x-, y-, and z-axes) orientations. Rotation impaired within-modal recognition accuracy in both vision and touch, but not cross-modal recognition accuracy. Within-modally, visual recognition accuracy was reduced by rotation about the x- and y-axes more than the z-axis, whilst haptic recognition was equally affected by rotation about all three axes. Cross-modal (but not within-modal) accuracy correlated with spatial (but not object) imagery scores. CONCLUSIONS/SIGNIFICANCE: The viewpoint-independence of cross-modal object identification points to its mediation by a high-level abstract representation. The correlation between spatial imagery scores and cross-modal performance suggest that construction of this high-level representation is linked to the ability to perform spatial transformations. Within-modal viewpoint-dependence appears to have a different basis in vision than in touch, possibly due to surface occlusion being important in vision but not touch

Removing leakage-induced correlated errors in superconducting quantum error correction

Quantum computing can become scalable through error correction, but logical error rates only decrease with system size when physical errors are sufficiently uncorrelated. During computation, unused high energy levels of the qubits can become excited, creating leakage states that are long-lived and mobile. Particularly for superconducting transmon qubits, this leakage opens a path to errors that are correlated in space and time. Here, we report a reset protocol that returns a qubit to the ground state from all relevant higher level states. We test its performance with the bit-flip stabilizer code, a simplified version of the surface code for quantum error correction. We investigate the accumulation and dynamics of leakage during error correction. Using this protocol, we find lower rates of logical errors and an improved scaling and stability of error suppression with increasing qubit number. This demonstration provides a key step on the path towards scalable quantum computing

Transcriptome Kinetics Is Governed by a Genome-Wide Coupling of mRNA Production and Degradation: A Role for RNA Pol II

Transcriptome dynamics is governed by two opposing processes, mRNA production and degradation. Recent studies found that changes in these processes are frequently coordinated and that the relationship between them shapes transcriptome kinetics. Specifically, when transcription changes are counter-acted with changes in mRNA stability, transient fast-relaxing transcriptome kinetics is observed. A possible molecular mechanism underlying such coordinated regulation might lay in two RNA polymerase (Pol II) subunits, Rpb4 and Rpb7, which are recruited to mRNAs during transcription and later affect their degradation in the cytoplasm. Here we used a yeast strain carrying a mutant Pol II which poorly recruits these subunits. We show that this mutant strain is impaired in its ability to modulate mRNA stability in response to stress. The normal negative coordinated regulation is lost in the mutant, resulting in abnormal transcriptome profiles both with respect to magnitude and kinetics of responses. These results reveal an important role for Pol II, in regulation of both mRNA synthesis and degradation, and also in coordinating between them. We propose a simple model for production-degradation coupling that accounts for our observations. The model shows how a simple manipulation of the rates of co-transcriptional mRNA imprinting by Pol II may govern genome-wide transcriptome kinetics in response to environmental changes