This study confirms the under-use of warfarin, but also adds to published reports in several regards. It showed that risk stratification, the guidepost for treatment in international guidelines, had little effect on warfarin use, and that age >80 years and AF classification (permanent/persistent) are factors that influence warfarin use.

A cellular pre-mRNA undergoes various post-transcriptional processing events, including capping, splicing and polyadenylation prior to nuclear export. Splicing is particularly important for mRNA nuclear export as two distinct multi-protein complexes, known as human TREX (hTREX) and the exon-junction complex (EJC), are recruited to the mRNA in a splicing-dependent manner. In contrast, a number of Kaposi's sarcoma–associated herpesvirus (KSHV) lytic mRNAs lack introns and are exported by the virus-encoded ORF57 protein. Herein we show that ORF57 binds to intronless viral mRNAs and functions to recruit the complete hTREX complex, but not the EJC, in order assemble an export component viral ribonucleoprotein particle (vRNP). The formation of this vRNP is mediated by a direct interaction between ORF57 and the hTREX export adapter protein, Aly. Aly in turn interacts directly with the DEAD-box protein UAP56, which functions as a bridge to recruit the remaining hTREX proteins to the complex. Moreover, we show that a point mutation in ORF57 which disrupts the ORF57-Aly interaction leads to a failure in the ORF57-mediated recruitment of the entire hTREX complex to the intronless viral mRNA and inhibits the mRNAs subsequent nuclear export and virus replication. Furthermore, we have utilised a trans-dominant Aly mutant to prevent the assembly of the complete ORF57-hTREX complex; this results in a vRNP consisting of viral mRNA bound to ORF57, Aly and the nuclear export factor, TAP. Strikingly, although both the export adapter Aly and the export factor TAP were present on the viral mRNP, a dramatic decrease in intronless viral mRNA export and virus replication was observed in the absence of the remaining hTREX components (UAP56 and hTHO-complex). Together, these data provide the first direct evidence that the complete hTREX complex is essential for the export of KSHV intronless mRNAs and infectious virus production.

In this cross-section of United States hospitals, lower than anticipated use of LMWH, insufficient bridging from UFH or LMWH to warfarin, and continuation of anticoagulation after hospitalization were all problems discovered with the treatment of VTE. Physician knowledge, attitudes, and beliefs are partially responsible for the gap between actual practice and international guidelines. These results suggest that hospitals should evaluate their adherence to international VTE treatment guidelines and develop strategies to optimize antithrombotic therapy.

OBJECTIVE: To evaluate the change in hemoglobin A1C (A1C) in patients with type 2 diabetes switched from coadministration of a sulfonylurea (SU), glyburide or glipizide, and metformin (SU+Met) to a single glyburide-metformin tablet.METHODS: A retrospective cohort study design of patients with type 2 diabetes treated at 3 Veterans Affairs Medical Centers and 1 Department of Defense Medical Center was utilized. One hundred percent of patients receiving glyburidemetformin tablets were screened for inclusion. Patients with at least 6 months of prior SU+Met combination therapy and a baseline A1C measured within 35 days prior to or 3 days after switch to glyburide-metformin tablets were included. At least one documented follow-up A1C at ≥90 days after the switch to glyburidemetformin was required for inclusion. Glycemic control, complications, lipid parameters, concomitant medications, and weight were analyzed prior to and following the switch to glyburide-metformin.

The study by Kesselheim et al, 1 about physicians' perspectives on US Food and Drug Administration (FDA) approval standards and off-label drug marketing, calls attention to the importance of medical evidence and drug safety, issues that were central to Schwartz's research and advocacy. The study found that most physicians oppose any weakening of FDA approval standards and support the agency's current restrictions on off-label marketing. 1 Most of the survey respondents thought it would be a "bad" or "terrible" idea for the agency to allow off-label promotion by sales representatives in physicians' offices, drug advertisements in medical journals, or direct-to-consumer advertisements. The clarity of the wording in the survey is typical of Lisa's work. Among many other activities, Lisa and Steve ran courses for journalists, training them to be appropriately skeptical about purported medical breakthroughs, and to better communicate the benefits and harms of medical tests and treatments. Through their work, Schwartz and Woloshin charted a course for physicians and patients to move forward, with less waste and harm through overdiagnosis and overtreatment, less hype about medications that offer no meaningful benefits, and more use of effective care. As they noted in a recent essay, "asking 'Is less more?' has resulted in a profound shift in the ethos of medicine: a recognition that health care truly is a doubleedged sword that can harm as well as benefit patients." 3 We are reminded of why we become physicians, and of the work that remains to be done. Medicine and the world have suffered a great loss with Lisa's untimely death. We will all miss her terribly as we seek to carry on her legacy.

The herpesvirus saimiri (HVS) ORF57 protein binds viral RNA, enabling the efficient nuclear export of intronless viral mRNAs. However, it is not known how ORF57 recognizes these viral mRNAs. In this study, a systematic evolution of ligands by exponential enrichment (SELEX) approach was used to select RNA sequences that are preferentially bound by the ORF57 protein.Results identified a recurring motif, GAAGRG, within the majority of selected RNAs, which is also present in many late HVS mRNAs. RNA immunopreciptations demonstrated that disruption of this motif within a viral intronless RNA ablates ORF57 binding. These data suggest that the GAAGRG motif may be required within a HVS intronless mRNA for recognition by the ORF57 protein.The herpesvirus saimiri (HVS) ORF57 protein is homologous to gene products identified in all classes of herpesviruses (Bello et al., 1999;Perera et al., 1994;Sacks et al., 1985;Winkler et al., 1994). ORF57 is a multifunctional protein that regulates viral gene expression at the post-transcriptional level (Boyne et al., 2008a;Boyne & Whitehouse, 2006a;Cooper et al., 1999;Goodwin et al., 1999;Goodwin & Whitehouse, 2001;Whitehouse et al., 1998). The primary role of ORF57 is to mediate the nuclear export of HVS intronless transcripts. This event is essential for viral replication, as intronless transcripts are retained in the nucleus following transcription due to the splicingdependent nature of cellular mRNA export. To facilitate this function, ORF57 shuttles between the nucleus and the cytoplasm, trafficks through the nucleolus, binds viral RNA and interacts with various cellular nuclear import/export proteins (Boyne & Whitehouse, 2006b;Goodwin et al., 1999;Williams et al., 2005). HVS ORF57 comprises several functional domains, which are conserved between its viral homologues (Boyne et al., 2008a), including two nuclear localization signals (Boyne & Whitehouse, 2006b), a leucine-rich nuclear export signal (Goodwin & Whitehouse, 2001) and carboxy-terminal zinc finger-like and hydrophobic GLFF domains (Goodwin et al., 2000). Furthermore, the RNA-binding domain has been mapped to an amino terminus arginine-rich region (Goodwin et al., 1999). However, how ORF57 specifically recognizes and binds viral intronless mRNAs is yet to be elucidated. At present, no specific response element has been identified in any HVS mRNAs; therefore, in this study, we have utilized a systematic evolution of ligands by exponential enrichment (SELEX) approach (Joyce, 1994;Stoltenburg et al., 2007) to identify RNA sequences that ORF57 specifically binds from a random pool. Results identified a core response element, GAAGRG (where R is a purine). Moreover, mutation of this element within the intronless ORF47 mRNA ablated ORF57 binding.To identify RNA sequences recognized by ORF57, a SELEX screen was performed. SELEX utilizes the ability to create different aptamers quickly by generating a random pool and selecting those species that have an increased affinity towards a target (Stoltenburg et al., 2007). Selected RNAs...

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Herpesvirus saimiri (HVS) ORF57 nucleocytoplasmic shuttle protein binds viral RNA and interacts with the cellular nuclear export adaptor protein, Aly, to access the TAP-mediated nuclear export pathway. This enables the efficient nuclear export of HVS intronless mRNAs. Herein, we extend these studies and demonstrate that ORF57 recruits several members of hTREX, namely Aly, UAP56 and hTHO-complex proteins, onto the viral mRNAs to assemble an export-competent ribonucleoprotein particle. Moreover, using a transdominant form of Aly which inhibits UAP56 and hTHO-complex association with viral intronless mRNA, we show that complete hTREX recruitment is required for efficient HVS mRNA nuclear export and replication.In contrast with cellular genes, the majority of the herpesvirus lytically expressed genes lack introns. Herpesviruses replicate in the host cell nucleus and therefore require their intronless mRNAs to be efficiently exported from the nucleus to allow translation. To undergo efficient nuclear export, cellular mRNAs undergo various post-transcriptional processing events, including capping, splicing and polyadenylation (Bentley, 2005;Erkmann & Kutay, 2004;Vargas et al., 2005). It is evident that splicing is particularly important for mRNA nuclear export (Luo & Reed, 1999). The distinct multi-protein complexes hTREX and the exon-exon junction complex are both recruited to mRNA in a cap-and splicing-dependent manner. hTREX, which comprises Aly/REF, UAP56 and the multi-protein hTHO-complex, is pivotal in directing nuclear export of mRNA (Cheng et al., 2006;Masuda et al., 2005). Once bound to mRNA, Aly stimulates recruitment of the mRNA export factor, TAP . TAP interacts with p15 (Fribourg et al., 2001) and nucleoporins, providing the connection between the ribonucleoprotein particle (RNP) and the nuclear pore (Bachi et al., 2000;Grant et al., 2002;Huang & Steitz, 2001).To facilitate efficient viral intronless mRNA export, herpesviruses encode a conserved protein which has an essential role in post-transcriptional mechanisms (Bello et al., 1999;Boyne et al., 2008a;Boyne & Whitehouse, 2006a;Sandri-Goldin, 2004;Smith et al., 2005;Swaminathan, 2005). Herpesvirus saimiri (HVS) ORF57 binds viral mRNA and shuttles between the nucleus and cytoplasm, promoting nuclear export of viral intronless mRNAs (Boyne et al., 2008a;Boyne & Whitehouse, 2006b;Colgan et al., 2009;Cooper et al., 1999;Goodwin et al., 1999Goodwin et al., , 2000Goodwin & Whitehouse, 2001;Whitehouse et al., 1998). We have demonstrated that ORF57 interacts with Aly, providing the connection between the viral RNP and the nuclear export factor, TAP. Moreover, disruption of the TAP-mediated nuclear export pathway had a profound effect on HVS replication (Williams et al., 2005). This suggests that the ORF57-Aly-TAP interaction is required for the efficient nuclear export of intronless transcripts.Herein, we demonstrate that ORF57 associates with other core components of hTREX forming an export competent viral RNP. Moreover, we show that hTREX recruitment onto the...