The prevention of injury associated with falls in older people is a public health target in many countries around the world. Although there is good evidence that interventions such as multifactorial ...fall prevention and individually prescribed exercise are effective in reducing falls, the effect on serious injury rates is unclear.1,2 Historically, trials have not been adequately powered to detect injury endpoints, and variations in case definition across trials have hindered meta‐analysis.1 It is possible that fall‐prevention strategies have limited effect on falls that result in injuries or are ineffective in populations who are at a higher risk of injury. Further research is required to determine whether fall‐prevention interventions can reduce serious injuries.
Prevention of Falls Network Europe (ProFaNE) is a collaborative project to reduce the burden of fall injury in older people through excellence in research and promotion of best practice (http://www.profane.eu.org). The European Commission funds the network, which links clinicians, members of the public, and researchers worldwide. The aims are to identify major gaps in knowledge in fall injury prevention and to facilitate the collaboration necessary for large‐scale clinical research activity, including clinical trials, comparative research, and prospective meta‐analysis. Work is being undertaken in a 4‐year program. As a first step, the development of a common set of outcome definitions and measures for future trials or meta‐analysis was considered.
Although several macrolide antibiotics are proarrhythmic and associated with an increased risk of sudden cardiac death, azithromycin is thought to have minimal cardiotoxicity. However, published ...reports of arrhythmias suggest that azithromycin may increase the risk of cardiovascular death.
We studied a Tennessee Medicaid cohort designed to detect an increased risk of death related to short-term cardiac effects of medication, excluding patients with serious noncardiovascular illness and person-time during and shortly after hospitalization. The cohort included patients who took azithromycin (347,795 prescriptions), propensity-score-matched persons who took no antibiotics (1,391,180 control periods), and patients who took amoxicillin (1,348,672 prescriptions), ciprofloxacin (264,626 prescriptions), or levofloxacin (193,906 prescriptions).
During 5 days of therapy, patients taking azithromycin, as compared with those who took no antibiotics, had an increased risk of cardiovascular death (hazard ratio, 2.88; 95% confidence interval CI, 1.79 to 4.63; P<0.001) and death from any cause (hazard ratio, 1.85; 95% CI, 1.25 to 2.75; P=0.002). Patients who took amoxicillin had no increase in the risk of death during this period. Relative to amoxicillin, azithromycin was associated with an increased risk of cardiovascular death (hazard ratio, 2.49; 95% CI, 1.38 to 4.50; P=0.002) and death from any cause (hazard ratio, 2.02; 95% CI, 1.24 to 3.30; P=0.005), with an estimated 47 additional cardiovascular deaths per 1 million courses; patients in the highest decile of risk for cardiovascular disease had an estimated 245 additional cardiovascular deaths per 1 million courses. The risk of cardiovascular death was significantly greater with azithromycin than with ciprofloxacin but did not differ significantly from that with levofloxacin.
During 5 days of azithromycin therapy, there was a small absolute increase in cardiovascular deaths, which was most pronounced among patients with a high baseline risk of cardiovascular disease. (Funded by the National Heart, Lung, and Blood Institute and the Agency for Healthcare Quality and Research Centers for Education and Research on Therapeutics.).
This article develops a model that speaks to the goals and methods of financial stability policies. There are three main points. First, from a normative perspective, the model defines the fundamental ...market failure to be addressed, namely, that unregulated private money creation can lead to an externality in which intermediaries issue too much short-term debt and leave the system excessively vulnerable to costly financial crises. Second, it shows how in a simple economy where commercial banks are the only lenders, conventional monetary policy tools such as open-market operations can be used to regulate this externality, whereas in more advanced economies it may be helpful to supplement monetary policy with other measures. Third, from a positive perspective, the model provides an account of how monetary policy can influence bank lending and real activity, even in a world where prices adjust frictionlessly and there are other transactions media besides bank-created money that are outside the control of the central bank.
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.
Generating a functional proteome requires the ribosome to carefully regulate disparate co-translational processes that determine the fate of nascent polypeptides. With protein synthesis being ...energetically expensive, the ribosome must balance the costs of efficiently making a protein with those of properly folding it. Emerging as a primary means of regulating this trade-off is the nonuniform rate of translation elongation that defines translation kinetics. The varying speeds with which the ribosome progresses along a transcript have been implicated in several aspects of protein biogenesis, including co-translational protein folding and translational fidelity, as well as gene expression by mediating mRNA decay and protein quality control pathways. The optimal translation kinetics required to efficiently execute these processes can be distinct. Thus, the ribosome is tasked with tightly regulating translation kinetics to balance these processes while maintaining adaptability for changing cellular conditions. In this review, we first discuss the regulatory role of translation elongation in protein biogenesis and what factors influence elongation kinetics. We then describe how changes in translation kinetics signal downstream pathways that dictate the fate of nascent polypeptides. By regulating these pathways, the kinetics of translation elongation has emerged as a critical tool for driving gene expression and maintaining proteostasis through varied mechanisms, including nascent chain folding and binding different ribosome-associated machinery. Indeed, a growing number of examples demonstrate the important role of local changes in elongation kinetics in modulating the pathophysiology of human disease.
Long-acting opioids increase the risk of unintentional overdose deaths but also may increase mortality from cardiorespiratory and other causes.
To compare all-cause mortality for patients with ...chronic noncancer pain who were prescribed either long-acting opioids or alternative medications for moderate to severe chronic pain.
Retrospective cohort study between 1999 and 2012 of Tennessee Medicaid patients with chronic noncancer pain and no evidence of palliative or end-of-life care.
Propensity score-matched new episodes of prescribed therapy for long-acting opioids or either analgesic anticonvulsants or low-dose cyclic antidepressants (control medications).
Total and cause-specific mortality as determined from death certificates. Adjusted hazard ratios (HRs) and risk differences (difference in incidence of death) were calculated for long-acting opioid therapy vs control medication.
There were 22,912 new episodes of prescribed therapy for both long-acting opioids and control medications (mean SD age, 48 11 years; 60% women). The long-acting opioid group was followed up for a mean 176 days and had 185 deaths and the control treatment group was followed up for a mean 128 days and had 87 deaths. The HR for total mortality was 1.64 (95% CI, 1.26-2.12) with a risk difference of 68.5 excess deaths (95% CI, 28.2-120.7) per 10,000 person-years. Increased risk was due to out-of-hospital deaths (154 long-acting opioid, 60 control deaths; HR, 1.90; 95% CI, 1.40-2.58; risk difference, 67.1; 95% CI, 30.1-117.3) excess deaths per 10,000 person-years. For out-of-hospital deaths other than unintentional overdose (120 long-acting opioid, 53 control deaths), the HR was 1.72 (95% CI, 1.24-2.39) with a risk difference of 47.4 excess deaths (95% CI, 15.7-91.4) per 10,000 person-years. The HR for cardiovascular deaths (79 long-acting opioid, 36 control deaths) was 1.65 (95% CI, 1.10-2.46) with a risk difference of 28.9 excess deaths (95% CI, 4.6-65.3) per 10,000 person-years. The HR during the first 30 days of therapy (53 long-acting opioid, 13 control deaths) was 4.16 (95% CI, 2.27-7.63) with a risk difference of 200 excess deaths (95% CI, 80-420) per 10,000 person-years.
Prescription of long-acting opioids for chronic noncancer pain, compared with anticonvulsants or cyclic antidepressants, was associated with a significantly increased risk of all-cause mortality, including deaths from causes other than overdose, with a modest absolute risk difference. These findings should be considered when evaluating harms and benefits of treatment.
Abstract
We explore the interplay between trade-invoicing patterns and the pricing of safe assets in different currencies. Our theory highlights the following points: (i) a currency’s role as a unit ...of account for invoicing decisions is complementary to its role as a safe store of value; (ii) this complementarity can lead to the emergence of a single dominant currency in trade invoicing and global banking, even when multiple large candidate countries share similar economic fundamentals; (iii) firms in emerging-market countries endogenously take on currency mismatches by borrowing in the dominant currency; and (iv) the expected return on dominant-currency safe assets is lower than that on similarly safe assets denominated in other currencies, thereby bestowing an “exorbitant privilege” on the dominant currency. The theory thus provides a unified explanation for why a dominant currency is so heavily used in both trade invoicing and in global finance.
Black hole spacetimes, like the Kerr spacetime, admit both stable and plunging orbits, separated in parameter space by the separatrix. Determining the location of the separatrix is of fundamental ...interest in understanding black holes, and is of crucial importance for modeling extreme-mass-ratio inspirals. Previous numerical approaches to locating the Kerr separatrix were not always efficient or stable across all of parameter space. In this paper we show that the Kerr separatrix is the zero set of a single polynomial in parameter space. This gives two main results. First, we thoroughly analyze special cases (extreme Kerr, polar orbits, etc.), finding strict bounds on the limits of roots, and unifying a number of results in the literature. Second, we pose a stable numerical method which is guaranteed to quickly and robustly converge to the separatrix. This new approach is implemented in the Black Hole Perturbation Toolkit, and results in a ∼45× speedup over the prior robust approach.
We present accurate fits for the remnant properties of generically precessing binary black holes, trained on large banks of numerical-relativity simulations. We use Gaussian process regression to ...interpolate the remnant mass, spin, and recoil velocity in the seven-dimensional parameter space of precessing black-hole binaries with mass ratios q≤2, and spin magnitudes χ_{1}, χ_{2}≤0.8. For precessing systems, our errors in estimating the remnant mass, spin magnitude, and kick magnitude are lower than those of existing fitting formulae by at least an order of magnitude (improvement is also reported in the extrapolated region at high mass ratios and spins). In addition, we also model the remnant spin and kick directions. Being trained directly on precessing simulations, our fits are free from ambiguities regarding the initial frequency at which precessing quantities are defined. We also construct a model for remnant properties of aligned-spin systems with mass ratios q≤8, and spin magnitudes χ_{1}, χ_{2}≤0.8. As a byproduct, we also provide error estimates for all fitted quantities, which can be consistently incorporated into current and future gravitational-wave parameter-estimation analyses. Our model(s) are made publicly available through a fast and easy-to-use Python module called surfinBH.
In theories of gravity that include a scalar field, a compact object’s scalar charge is a crucial quantity since it controls dipole radiation, which can be strongly constrained by pulsar timing and ...gravitational wave observations. However, in most such theories, computing the scalar charge requires simultaneously solving the coupled, nonlinear metric and scalar field equations of motion. In this article, we prove that in linearly coupled Einstein-dilaton-Gauss-Bonnet gravity, a black hole’s scalar charge is completely determined by the horizon surface gravity times the Euler characteristic of the bifurcation surface, without solving any equations of motion. Within this theory, black holes announce their horizon topology and surface gravity to the rest of the Universe through the dilaton field. In our proof, a four-dimensional topological density descends to a two-dimensional topological density on the bifurcation surface of a Killing horizon. We also comment on how our proof can be generalized to other topological densities on general G-bundles, and to theories where the dilaton is nonlinearly coupled to the Euler density.
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