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.