Summary Overuse, which is defined as the provision of medical services that are more likely to cause harm than good, is a global problem that afflicts rich and poor countries alike. This article reviews the definition of overuse, methods for measuring overuse, harms from overuse, and the evidence for worldwide overuse of many types of services.

Ubiquitin is one of the most highly conserved proteins in eukaryotes and plays major biological roles as a post-translational protein modifier. Ubiquitin is also a natural constituent of plasma, and several lines of evidence suggest that extracellular ubiquitin is an immune modulator with anti-inflammatory properties. In addition, ubiquitin treatment has been shown to limit inflammation and reduce organ injury in various disease models and species in vivo. However, its mechanism of action is unknown. Here we show that extracellular ubiquitin is a natural CXC chemokine receptor 4 (CXCR4 and CD184) agonist. Extracellular ubiquitin promotes intracellular Ca 2؉ flux and reduces cAMP levels through a G protein-coupled receptor that signals via a G␣ i/o protein in THP1 cells. Toll-like receptor 4 stimulation reduces ubiquitin-binding sites, which enabled identification of four G␣ i/o PCRs as ubiquitin receptor candidates. Overexpression of candidate genes in HEK293 cells, gene silencing in THP1 cells, competition binding, and signaling studies with the CXCR4 agonist stromal cell-derived factor-1␣ (chemokine (CXC motif) ligand 12) and inhibitor AMD3100 identify CXCR4 as a functional ubiquitin receptor. Our finding uncovers a fundamentally new aspect of the role of ubiquitin in biology, has implications for the understanding of CXCR4-mediated events, and is expected to facilitate development of new therapeutic avenues for a variety of diseases.

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Although overuse in medicine is gaining increased attention, many questions remain unanswered. Dan Morgan and colleagues propose an agenda for coordinated research to improve our understanding of the problem Daniel J Morgan associate professor 1 , Shannon Brownlee writer 2 , Aaron L Leppin postdoctoral research fellow

BackgroundOvertreatment is a cause of preventable harm and waste in health care. Little is known about clinician perspectives on the problem. In this study, physicians were surveyed on the prevalence, causes, and implications of overtreatment.Methods2,106 physicians from an online community composed of doctors from the American Medical Association (AMA) masterfile participated in a survey. The survey inquired about the extent of overutilization, as well as causes, solutions, and implications for health care. Main outcome measures included: percentage of unnecessary medical care, most commonly cited reasons of overtreatment, potential solutions, and responses regarding association of profit and overtreatment.FindingsThe response rate was 70.1%. Physicians reported that an interpolated median of 20.6% of overall medical care was unnecessary, including 22.0% of prescription medications, 24.9% of tests, and 11.1% of procedures. The most common cited reasons for overtreatment were fear of malpractice (84.7%), patient pressure/request (59.0%), and difficulty accessing medical records (38.2%). Potential solutions identified were training residents on appropriateness criteria (55.2%), easy access to outside health records (52.0%), and more practice guidelines (51.5%). Most respondents (70.8%) believed that physicians are more likely to perform unnecessary procedures when they profit from them. Most respondents believed that de-emphasizing fee-for-service physician compensation would reduce health care utilization and costs.ConclusionFrom the physician perspective, overtreatment is common. Efforts to address the problem should consider the causes and solutions offered by physicians.

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Recently, we identified extracellular ubiquitin as an endogenous CXC chemokine receptor (CXCR) 4 agonist. However, the receptor selectivity and molecular basis of the CXCR4 agonist activity of ubiquitin are unknown, and functional consequences of CXCR4 activation with ubiquitin are poorly defined. Here, we provide evidence that ubiquitin and the cognate CXCR4 ligand stromal cell-derived factor (SDF)-1␣ do not share CXCR7 as a receptor. We further demonstrate that ubiquitin does not utilize the typical two-site binding mechanism of chemokine-receptor interactions, in which the receptor N terminus is important for ligand binding. CXCR4 activation with ubiquitin and SDF-1␣ lead to similar G␣ iresponses and to a comparable magnitude of phosphorylation of ERK-1/2, p90 ribosomal S6 kinase-l and Akt, although phosphorylations occur more transiently after activation with ubiquitin. Despite the similarity of signal transduction events after activation of CXCR4 with both ligands, ubiquitin possesses weaker chemotactic activity than SDF-l␣ in cell migration assays and does not interfere with productive entry of HIV-1 into P4.R5 multinuclear activation of galactosidase indicator cells. Unlike SDF-1␣, ubiquitin lacks interactions with an N-terminal CXCR4 peptide in NMR spectroscopy experiments. Binding and signaling studies in the presence of antibodies against the N terminus and extracellular loops 2/3 of CXCR4 confirm that the ubiquitin CXCR4 interaction is independent of the N-terminal receptor domain, whereas blockade of extracellular loops 2/3 prevents receptor binding and activation. Our findings define ubiquitin as a CXCR4 agonist, which does not interfere with productive cellular entry of HIV-1, and provide new mechanistic insights into interactions between CXCR4 and its natural ligands.