Cholesterol reduction from statin therapy has been one of the greatest public health successes in modern medicine. Simvastatin is among the most commonly used prescription medications. A ...non‐synonymous coding single‐nucleotide polymorphism (SNP), rs4149056, in SLCO1B1 markedly increases systemic exposure to simvastatin and the risk of muscle toxicity. This guideline explores the relationship between rs4149056 (c.521T>C, p.V174A) and clinical outcome for all statins. The strength of the evidence is high for myopathy with simvastatin. We limit our recommendations accordingly.
Clinical Pharmacology & Therapeutics (2012); 92 1, 112–117. doi:10.1038/clpt.2012.57
Summary Background Lifestyle changes soon after diagnosis might improve outcomes in patients with type 2 diabetes mellitus, but no large trials have compared interventions. We investigated the ...effects of diet and physical activity on blood pressure and glucose concentrations. Methods We did a randomised, controlled trial in southwest England in adults aged 30–80 years in whom type 2 diabetes had been diagnosed 5–8 months previously. Participants were assigned usual care (initial dietary consultation and follow-up every 6 months; control group), an intensive diet intervention (dietary consultation every 3 months with monthly nurse support), or the latter plus a pedometer-based activity programme, in a 2:5:5 ratio. The primary endpoint was improvement in glycated haemoglobin A1c (HbA1c ) concentration and blood pressure at 6 months. Analysis was done by intention to treat. This study is registered, number ISRCTN92162869. Findings Of 593 eligible individuals, 99 were assigned usual care, 248 the diet regimen, and 246 diet plus activity. Outcome data were available for 587 (99%) and 579 (98%) participants at 6 and 12 months, respectively. At 6 months, glycaemic control had worsened in the control group (mean baseline HbA1c percentage 6·72, SD 1·02, and at 6 months 6·86, 1·02) but improved in the diet group (baseline-adjusted difference in percentage of HbA1c −0·28%, 95% CI −0·46 to −0·10; p=0·005) and diet plus activity group (−0·33%, −0·51 to −0·14; p<0·001). These differences persisted to 12 months, despite less use of diabetes drugs. Improvements were also seen in bodyweight and insulin resistance between the intervention and control groups. Blood pressure was similar in all groups. Interpretation An intensive diet intervention soon after diagnosis can improve glycaemic control. The addition of an activity intervention conferred no additional benefit. Funding Diabetes UK and the UK Department of Health.
Simvastatin is among the most commonly used prescription medications for cholesterol reduction. A single coding single‐nucleotide polymorphism, rs4149056T>C, in SLCO1B1 increases systemic exposure to ...simvastatin and the risk of muscle toxicity. We summarize evidence from the literature supporting this association and provide therapeutic recommendations for simvastatin based on SLCO1B1 genotype. This article is an update to the 2012 Clinical Pharmacogenetics Implementation Consortium guideline for SLCO1B1 and simvastatin‐induced myopathy.
Clinical Pharmacology & Therapeutics (2014); 96 4, 423–428. doi:10.1038/clpt.2014.125
Numerous pharmacogenetic clinical guidelines and recommendations have been published, but barriers have hindered the clinical implementation of pharmacogenetics. The Translational Pharmacogenetics ...Program (TPP) of the National Institutes of Health (NIH) Pharmacogenomics Research Network was established in 2011 to catalog and contribute to the development of pharmacogenetic implementations at eight US healthcare systems, with the goal to disseminate real‐world solutions for the barriers to clinical pharmacogenetic implementation. The TPP collected and normalized pharmacogenetic implementation metrics through June 2015, including gene–drug pairs implemented, interpretations of alleles and diplotypes, numbers of tests performed and actionable results, and workflow diagrams. TPP participant institutions developed diverse solutions to overcome many barriers, but the use of Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines provided some consistency among the institutions. The TPP also collected some pharmacogenetic implementation outcomes (scientific, educational, financial, and informatics), which may inform healthcare systems seeking to implement their own pharmacogenetic testing programs.
There is a growing body of evidence that links nutrition to muscle mass, strength and function in older adults, suggesting that it has an important role to play both in the prevention and management ...of sarcopenia. This review summarises the discussions of a working group ESCEO working group meeting 8th September 2016 that met to review current evidence and to consider its implications for preventive and treatment strategies. The review points to the importance of ‘healthier’ dietary patterns that are adequate in quality in older age, to ensure sufficient intakes of protein, vitamin D, antioxidant nutrients and long-chain polyunsaturated fatty acids. In particular, there is substantial evidence to support the roles of dietary protein and physical activity as key anabolic stimuli for muscle protein synthesis. However, much of the evidence is observational and from high-income countries. Further high-quality trials, particularly from more diverse populations, are needed to enable an understanding of dose and duration effects of individual nutrients on function, to elucidate mechanistic links, and to define optimal profiles and patterns of nutrient intake for older adults.
We report new experimental data on the composition of magmatic amphiboles synthesised from a variety of granite (sensu lato) bulk compositions at near-solidus temperatures and pressures of ...0.8–10 kbar. The total aluminium content (Al
tot
) of the synthetic calcic amphiboles varies systematically with pressure (
P
), although the relationship is nonlinear at low pressures (<2.5 kbar). At higher pressures, the relationship resembles that of other experimental studies, which suggests of a general relationship between Al
tot
and P that is relatively insensitive to bulk composition. We have developed a new Al-in-hornblende geobarometer that is applicable to granitic rocks with the low-variance mineral assemblage: amphibole + plagioclase (An
15–80
) + biotite + quartz + alkali feldspar + ilmenite/titanite + magnetite + apatite. Amphibole analyses should be taken from the rims of grains, in contact with plagioclase and in apparent textural equilibrium with the rest of the mineral assemblage at temperatures close to the haplogranite solidus (725 ± 75 °C), as determined from amphibole–plagioclase thermometry. Mean amphibole rim compositions that meet these criteria can then be used to calculate
P
(in kbar) from Al
tot
(in atoms per formula unit, apfu) according to the expression:
P
kbar
=
0.5
+
0.331
8
×
Al
tot
+
0.995
4
×
Al
tot
2
This expression recovers equilibration pressures of our calibrant dataset, comprising both new and published experimental and natural data, to within ±16 % relative uncertainty. An uncertainty of 10 % relative for a typical Al
tot
value of 1.5 apfu translates to an uncertainty in pressure estimate of 0.5 kbar, or 15 % relative. Thus the accuracy of the barometer expression is comparable to the precision with which near-solidus amphibole rim composition can be characterised.
New insights into the Late Precambrian-latest Devonian evolution of the Pacific margin of Gondwana are obtained by treating the margin in terms of three key tectonic elements: i) the in situ part of ...the Ross Orogen of Eastern Antarctica (Wilson Terrane) built on, and fringing, older crust; ii) the largely in situ southern Tasmanides of eastern Australia; and iii) offshore basement and island arc terranes now accreted either to the Ross Orogen, the Tuhua Orogen of southwestern New Zealand or, in one case, to the Australian Tasmanides. Detailed correlations between these elements suggest that the onset of convergence was essentially simultaneous along the margin over an original distance of ~1000 km. The first appearance of subduction-related igneous rocks occurred at ~540–530 Ma in the Tasmanides; ~535–530 Ma in the Tiger Arc of northern Victoria Land; and 550 Ma in southern Victoria Land of the Ross Orogen.
New correlations of this paper suggest possible but largely unconstrained trajectories of offshore terranes. The Bowers Terrane was accreted to the East Gondwana margin at 491-489 Ma, producing the main Ross Orogeny. The adjoining Takaka Terrane had docked briefly with that margin at ~497–494 Ma (Haupiri Disturbance in New Zealand) before crustal extension rifted it oceanward to drift away in the latest Cambrian to become amalgamated with the sedimentary Buller Terrane at ~387 Ma. The West Tasmania Terrane was accreted to the East Gondwana margin beginning at~500 Ma (generating phase 3 of the Tyennan Orogeny) and the connected Selwyn Block to the Tasmanides at ~500 Ma (main Delamerian Orogeny).
Our new interpretations suggest that previous lithological correlations of subduction-related volcanics between the Ross Orogen and southern Tasmanides did not take into account major rollback in the Tasmanides from ~514 to ~503 Ma. Similarly, they suggest that the ~550–480 Ma Granite Harbour Intrusive roots of the continental margin Ross Arc are not correlatives of 514, 505 and ~495–470 Ma granites intruding the Kanmantoo Group in the Delamerian Orogen of South Australia, either in time or in tectonic setting. We also recognize an early (~520–516 Ma) boninitic infant arc event in the outboard West Tasmania, Bowers, and Takaka terranes that predated ~500 Ma more mature arcs in the last two terranes. Arc-related magmatism in the Ross Orogen reflects the interplay between two main subduction systems — that which generated the Ross Arc and an outboard one that generated intraoceanic arcs.
Three major turbidite fan systems developed along the East Gondwana margin as responses to major deformations. Early Cambrian fan system 1 postdates the Beardmore Orogeny and includes the Kanmantoo Group in the Delamerian Orogen and the Berg and upper Priestley formations in the Wilson Terrane. Cambrian-Ordovician fan system 2 (the Robertson Bay Group, the Swanson Group in Marie Byrd Land, the Greenland Group in the Buller Terrane and the St Arnaud Group in the Delamerian Orogen) and Lower-Middle Ordovician fan system 3 (turbidites of the Eastern Lachlan Orogen, the Buller Terrane (New Zealand) and East Tasmania Terrane) both postdate different parts of the Ross Orogeny. Cessation of fan system 3 at ~460-458 Ma correlates with ‘accretion’ of the Robertson Bay Terrane in northern Victoria Land.
The presence or absence of a quantum critical point and its location in the phase diagram of high-temperature superconductors have been subjects of intense scrutiny. Clear evidence for quantum ...criticality, particularly in the transport properties, has proved elusive because the important low-temperature region is masked by the onset of superconductivity. We present measurements of the low-temperature in-plane resistivity of several highly doped La2-xSrxCuO4 single crystals in which the superconductivity had been stripped away by using high magnetic fields. In contrast to other quantum critical systems, the resistivity varies linearly with temperature over a wide doping range with a gradient that scales monotonically with the superconducting transition temperature. It is maximal at a critical doping level (pc) approximately 0.19 at which superconductivity is most robust. Moreover, its value at pc corresponds to the onset of quasi-particle incoherence along specific momentum directions, implying that the interaction that first promotes high-temperature superconductivity may ultimately destroy the very quasi-particle states involved in the superconducting pairing.
The Integrated Science Investigation of the Sun (ISIS) is a complete science investigation on the Solar Probe Plus (SPP) mission, which flies to within nine solar radii of the Sun’s surface. ISIS ...comprises a two-instrument suite to measure energetic particles over a very broad energy range, as well as coordinated management, science operations, data processing, and scientific analysis. Together, ISIS observations allow us to explore the mechanisms of energetic particles dynamics, including their: (1) Origins—defining the seed populations and physical conditions necessary for energetic particle acceleration; (2) Acceleration—determining the roles of shocks, reconnection, waves, and turbulence in accelerating energetic particles; and (3) Transport—revealing how energetic particles propagate from the corona out into the heliosphere. The two ISIS Energetic Particle Instruments measure lower (EPI-Lo) and higher (EPI-Hi) energy particles. EPI-Lo measures ions and ion composition from ∼20 keV/nucleon–15 MeV total energy and electrons from ∼25–1000 keV. EPI-Hi measures ions from ∼1–200 MeV/nucleon and electrons from ∼0.5–6 MeV. EPI-Lo comprises 80 tiny apertures with fields-of-view (FOVs) that sample over nearly a complete hemisphere, while EPI-Hi combines three telescopes that together provide five large-FOV apertures. ISIS observes continuously inside of 0.25 AU with a high data collection rate and burst data (EPI-Lo) coordinated with the rest of the SPP payload; outside of 0.25 AU, ISIS runs in low-rate science mode whenever feasible to capture as complete a record as possible of the solar energetic particle environment and provide calibration and continuity for measurements closer in to the Sun. The ISIS Science Operations Center plans and executes commanding, receives and analyzes all ISIS data, and coordinates science observations and analyses with the rest of the SPP science investigations. Together, ISIS’ unique observations on SPP will enable the discovery, untangling, and understanding of the important physical processes that govern energetic particles in the innermost regions of our heliosphere, for the first time. This paper summarizes the ISIS investigation at the time of the SPP mission Preliminary Design Review in January 2014.
Plasmids are important drivers of bacterial evolution, but it is challenging to understand how plasmids persist over the long term because plasmid carriage is costly. Classical models predict that ...horizontal transfer is necessary for plasmid persistence, but recent work shows that almost half of plasmids are non-transmissible. Here we use a combination of mathematical modelling and experimental evolution to investigate how a costly, non-transmissible plasmid, pNUK73, can be maintained in populations of Pseudomonas aeruginosa. Compensatory adaptation increases plasmid stability by eliminating the cost of plasmid carriage. However, positive selection for plasmid-encoded antibiotic resistance is required to maintain the plasmid by offsetting reductions in plasmid frequency due to segregational loss. Crucially, we show that compensatory adaptation and positive selection reinforce each other's effects. Our study provides a new understanding of how plasmids persist in bacterial populations, and it helps to explain why resistance can be maintained after antibiotic use is stopped.
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