A 76-year-old man with chronic renal disease was admitted to this hospital because of fever, worsening renal function,

and confusion. Brain imaging revealed a small amount of material with restricted diffusion layering in the occipital horns of the lateral ventricles.

A 65-year-old man presented with a 10-year history of involuntary movements of his left hand. Neurologic examinations showed hemichorea in his left arm (see video) that disappeared during sleep. Computed tomography of the brain revealed a calcified lesion in the right putamen (Panel A). T 2weighted magnetic resonance imaging of the brain showed mixed signal intensity, with a central core and a peripheral rim of decreased intensity in the right putamen (Panels B and C) that suggested cavernous angioma. The results of magnetic resonance angiography were normal. Oral intake of haloperidol, sodium valproate, and zonisamide did not improve the symptom. Hemichorea is an occasional complication of various vascular disorders affecting the contralateral basal ganglia, but this manifestation is usually transient. Putaminal cavernous angioma, a rare cause of hemichorea, can yield an intractable pathologic circuitry among the basal ganglia and cortical motor areas.

This article has no abstract; the first 100 words appear below. The landscape of therapy for hepatitis C virus (HCV) infection is changing rapidly. Until recently, the standard of care for HCV infection was a combination of peginterferon and ribavirin. Our increased understanding of the basic biology of HCV led to the identification of specific proteins involved in the replication of the virus. These proteins can be targeted by protease and polymerase inhibitors. Two years ago, the advent of protease inhibitors, such as telaprevir and boceprevir, profoundly affected the field.1,2 These agents improved the likelihood of cure but came with a number of inherent limitations. Protease inhibitors do not have . . .

An otherwise healthy 30-year-old man had been ill for 2 days when he presented with a temperature of 39C and reported passing dark urine (his case was noted in Bhatt et al., East African Medical Journal 1994;71:755-7). He reported taking no medication before coming to the hospital. Laboratory evaluation on admission was notable for a hemoglobin level of 7.6 g per deciliter, a serum urea nitrogen level of 4.8 mmol per liter (0.13 mg per deciliter), and a creatinine level of 89 mol per liter (1.0 mg per deciliter). The total bilirubin level was 15 mol per liter (0.88 mg per deciliter), and the conjugated bilirubin level 1 mol per liter (0.06 mg per deciliter). A urinary dipstick test was positive for blood but microscopical examination showed

no red blood cells (the dipstick test used could not differentiate red blood cells from hemoglobin). The blood smear showed 5% parasitemia of red blood cells with Plasmodium falciparum. Progressive clearance of his urine is shown, from dark brown on admission (T0, or zero hour) to yellow 42 hours after admission (T42). His condition improved on treatment with quinine, initially administered intravenously and then orally for a total of 7 days. He stayed in the hospital for 48 hours. The qualitative glucose-6-phosphate dehydrogenase (G6PD) level 28 days later was very low. Black-water fever is most often associated with the use of antimalarial medication, especially quinine, but in this patient, dark urine developed before quinine therapy, making this diagnosis less likely. As many Africans are heterozygotes for G6PD deficiency, which is thought to provide protection against malaria, this may be the cause of his hemolysis.

n this issue of the Journal, Donelan and colleagues1 report that primary care physicians and nurse practitioners often work side by side but inhabit different universes, at least perceptually. Daniel Kahneman, the psychologist and Nobel laureate who helped found the emerging field of behavioral economics, would find this unsurprising. He contends that all humans are influenced by powerful unconscious mental filters that shape how they perceive the world around them. 2 Given the heated debate over the roles of physicians and nurse practitioners in providing primary care in the United States,3 those filters are probably working overtime when these professionals reflect .

As the 2014 expansion of coverage mandated by the Affordable Care Act (ACA) looms larger, one question with no ready answer is how health care providers, policymakers, and payers will cope with an expected surge in patient demand for services. A shortage of primary care physicians to treat newly insured persons is the most immediate health workforce issue, but when added to the nation's population growth and more aging patients who require treatment, finding a practitioner may become an even more daunting challenge. In addition, only about one quarter of medical-school graduates plan careers as primary care physicians,1 and state scope-of-practice laws place limits on the clinical boundaries of advanced-practice registered nurses (APRNs), many of whom are providing primary care services in an array of settings.2 Organized medicine, spearheaded by the American Medical Association (AMA), strongly supports scope-of-practice laws as necessary to ensure patient safety and prevent APRNs from providing primary care without oversight by a physician. Nursing advocates take strong exception to scope-of-practice restrictions, particularly with respect to limits on their authority to prescribe drugs. They emphasize that an Institute of Medicine (IOM) report recommended that nurses should be free to practice to the full extent of their education and training.3,4Acknowledging that issuance of medical licenses has historically been the purview of states, Congress has not addressed the scope-of-practice matter,2,5,6 but ongoing activities by the Federal Trade Commission (FTC) related to scope-of-practice laws and their effect on competition in the health care marketplace have drawn the ire of organized medicine. In this article, I report on a recent estimate with regard to a growing shortage of physicians, the status of efforts to implement recommendations of an IOM report that charts a bold future for nursing, and the highly variable limits that state scope-of-practice laws impose on APRNs. I will discuss the intervention of the FTC into scope-of-practice matters, a new report by the National Governors Association that urges states to reexamine their scope-of-practice laws,7 and a 2012 scope-of-practice law8 enacted in Virginia that the AMA touts as a model for other states to follow. I will also cover a serious but ultimately unsuccessful dialogue organized by the Robert Wood Johnson Foundation that engaged a dozen physician and nursing leaders in search of common ground to resolve the issues that divide them. The collapse of this dialogue offered a snapshot of the unsettled states of discussions between national physician and nursing organizations over defining roles in an emerging model of team-based care that relies on interprofessional collaboration as one of its touchstones.

The physician workforce has grown more rapidly than the U.S. population over the past 30 years.9Nevertheless, the Association of American Medical Colleges estimates that by 2015 the nation will face a shortage of 62,100 physicians 33,100 primary care practitioners and 29,000 other specialists.10 A shortage of nurses evaporated during the recession, since many returned to the workforce, but nurse practitioners are a scarce resource in many areas. Actually, if the numbers of physicians and nurse practitioners were distributed more equally, there may be a sufficient number to care for most people, but because their practices are concentrated in urban and suburban locales, many rural and inner-city areas are left with too few practitioners in places where the need is often the greatest. In studies commissioned by the federal Agency for Healthcare Research and Quality, researchers at the Robert Graham Center estimated that 208,807 doctors, slightly fewer than one third of all full-time practicing physicians, 52% of nurse practitioners (55,625),11 and 43% of physician assistants (30,402) were providing primary care in 2010.10 The Department of Health and Human Services has been slow to provide its own workforce estimates because, as Secretary Kathleen Sebelius recently noted, of the complexities of measuring the supply of health professionals working across a range of health occupations and updating methods for estimating demand for health services in light of evolving health care delivery, demographic shifts, and the expansion of health insurance coverage.12 Sebelius was responding to a letter from Congress that requested an analysis of health care workforce needs . . . and . . . a workforce plan.13 Projecting the magnitude of greater demand for services is a difficult task, but research has consistently shown that persons with health insurance use more health care than do people without coverage. 14-16 The Congressional Budget Office estimated that, through the ACA, 15 million uninsured persons will secure coverage in 2014, and that number will increase to 35 million by 2016.17 Although the IOM report was issued more than 2 years ago, on October 5, 2010, it remains the road map that is guiding the future directions of nursing. The Robert Wood Johnson Foundation recognized that nurses needed a stronger educational base to press their case for greater clinical authority, so it approached the IOM in 2008 to propose a partnership between the two organizations to plot this course. The IOM agreed to the unique partnership, which was an unprecedented arrangement in its annals because, historically, it has closely protected its independence in conducting studies. The president of the IOM, Dr. Harvey V. Fineberg, described it as an experiment and offered a rationale in a foreword to the report: The possibility of strengthening the largest component of the health care workforce nurses to become partners and leaders in improving the delivery of care and the health care system as a whole inspired the IOM to partner with the Robert Wood Johnson Foundation . . . in creating the [Robert Wood Johnson Foundation] Initiative on the Future of Nursing, at the IOM. In this partnership, the IOM and [the Robert Wood Johnson Foundation] were in agreement that accessible, high-quality care cannot be achieved without exceptional nursing care and leadership. By working together, the two organizations sought to bring more credibility and visibility to the topic than either could by working alone. The organizations merged staff and resources in an unprecedented partnership to explore challenges central to the future of the nursing profession.3 The foundation's senior advisor for nursing, Dr. Susan Hassmiller, directed the staff of the IOM report and now oversees implementation of its recommendations through the Center to Champion Nursing in America,

an initiative of the AARP, the AARP Foundation, and the Robert Wood Johnson Foundation.18 Since 1982, the Robert Wood Johnson Foundation has granted $578 million to support schools of nursing and their faculty and students and to strengthen the quality of care once students are trained. The initiative (described above), which was chaired by former Health and Human Services Secretary Donna Shalala, stamped the institute's influential imprimatur on four key messages in its exhaustive 671-page report. First, nurses should practice to the full extent of their education and training through the elimination of historical, regulatory, and policy barriers. Second, nurses should achieve higher levels of education and training through an improved educational system that promotes seamless academic progress. Third, nurses should be full partners, with physicians and other health care professionals, in redesigning the system. Last, government should create a greater capacity to undertake effective workforce planning and policymaking through better data collection and information infrastructures. (The ACA created a National Health Care Workforce Commission, but Congress has not appropriated monies for its activation.) As the IOM report acknowledged, nursing has struggled throughout its history with definitional issues, particularly with respect to the various educational pathways that lead to an entry-level license to practice. Three pathways of varying lengths fulfill qualifications for initial licensure, all of which require the registered nurse to pass a nationally standardized examination in the state where he or she would practice. The most common pathway an associate's degree conferred by community colleges and nursing schools typically takes 2 to 3 years to complete and includes some exposure to clinical medicine. The same holds true for a 3-year diploma program offered by hospitals; this is the least common path to initial licensure and one that is being phased out. The third pathway is a 4-year bachelor of science in nursing degree that is usually offered by a university or college-based school of nursing. The typical curriculum includes the preparatory courses required in the associate's degree and diploma programs, plus an in-depth focus on the sciences, nursing research, public health, and clinical training. To obtain a master's degree, a nurse with a bachelor of science in nursing must put in an additional 500 to 700 supervised clinical hours to qualify as a nurse practitioner. By comparison, after earning a bachelor's degree, about 82,000 physician assistants who hold active state licenses to practice medicine under physician supervision average 2000 to 2200 hours of clinical training in a 26-month program with year-round instruction. More physician assistants and nurse practitioners, like physicians, are pursuing careers in specialties instead of primary care because of better compensation19 (and Cawley J: personal communication). In 2011, the median total annual compensation of general internists was $215,689; family practitioners, $200,114; nurse practitioners (general category), $93,977; and physician assistants (primary care), $92,635.20 The IOM report reinforced what nursing leaders had already recognized and were actively promoting: nurses need to secure higher degrees to upgrade their skills and increase opportunities to expand their clinical reach.21,22 This report recommended that 80% of nurses (up from about 50%) should hold at least a bachelor of science in nursing degree by 2020, in part because research shows lower mortality among surgical patients in hospitals with higher proportions of nurses with these degrees.23 Of the IOM's recommendations, progress has been greatest in increasing the number of students who pursue higher degrees; this trend had begun before the IOM report was launched. Enrollments in bachelor of science in nursing programs between 2006 and 2011 increased 26.6%, from 133,578 to 169,125 persons, according to the American Association of Colleges of Nursing.24

Over this same period, enrollments in master's programs increased 68.6%, from 56,028 to 94,480 persons; a master's degree is a minimum requirement for a nurse to qualify as an APRN. Matriculants in doctor of nursing practice programs increased 955.0%, from 862 to 9094 persons. However, 75,587 qualified applicants were denied admission to baccalaureate and graduate nursing programs in 2011 because of an insufficient number of faculty, clinical sites, and classrooms, and because of budget constraints. 24 In response to the growth of doctor of nursing practice programs, Dr. Roland Goetz, chairman of the board of the American Academy of Family Physicians (AAFP), said the profession worried that it was losing control of the word doctor.25,26 In response to this concern and related issues, the AMA launched a truth in advertising campaign because the association said some patients had difficulty distinguishing between a physician and a nonphysician doctor.27 A projected increase in numbers of nurse practitioners, as estimated by economist David Auerbach,28 is one solution to ameliorating the shortage of primary care physicians. APRNs assume four distinct practice roles. Data from 2008 (the latest published by the U.S. Health Resources and Services Administration) show that most are nurse practitioners (158,348), followed by clinical nurse specialists who care for special patient populations (59,242), certified registered nurse anesthetists (34,821), and certified nurse midwives (18,492).29 Nurse practitioners work in a variety of settings, including military facilities,30 nurse-managed health centers,31 and retail clinics.32-34 However, more than half are employed in private physician practices (27.9%) and hospitals (24.1%), according to a recent survey to which 13,562 (56.4% of the total number of nurse practitioners surveyed) responded.35 Many studies in the nursing literature provide support for the clinical performance of nurse practitioners.36-41 One recent systematic review gave them high marks for delivering safe, effective, quality care, but the authors also concluded that APRNs, in partnership with physicians and other providers . . . will need to move forward with evidence-based and more collaborative models of care delivery.42 The AMA43 has criticized studies that extol the care delivered by nurse practitioners, but that has not been the primary focus of its opposition to independent practice by nurse practitioners. Rather, the association has emphasized the greater educational preparation of physicians and noted how successful integrated systems (e.g., Geisinger Health System, Kaiser Permanente, and the Department of Veterans Affairs) employ many nurse practitioners who practice in physician-led teams. The conclusion of organized medicine is that medical doctors should lead these teams in a hierarchical structure with collaborative relationships with nurse practitioners and other nonphysician providers. Despite their intense opposition to independent practice by nurse practitioners, research by the AMA and state medical societies has shown that most states that allow such practices do not document which nurse practitioners actually have independent practices.44 One might speculate that, like physicians who are seeking financial shelter through hospital employment or other venues to weather the forces of consolidation, nurse practitioners could find themselves caught up in this same storm as they struggle to win independence and thus, in the end, they may prefer practicing in teams that seemingly would offer greater security. The IOM report identified as a serious barrier [to accessible care] overly restrictive scope-of-practice regulations for APRNs that vary by state. Noting the variability of these regulations a patchwork of state regulatory regimes, as they were characterized the IOM committee found that some states allow nurse practitioners to see patients and prescribe medications without physician supervision or collaboration, whereas the majority of state laws lag behind in this regard . . . for reasons that are not related to [APRNs']

ability, education or training, or safety concerns, but to the political decisions of the state in which they work. According to the AMA, 16 states and the District of Columbia allow APRNs to diagnose, treat, and refer patients and prescribe medications without physician supervision. Nine states require physician involvement for APRNs to prescribe, but not to diagnose and treat, and 24 states require physician

involvement for APRNs to diagnose, treat, and prescribe drugs44 (Figure 1FIGURE 1
Requirements for Physician Involvement in the Work of Advanced-Practice Registered Nurses.).

Because of the scope-of-practice restrictions imposed on nurse practitioners in many states, most nurse practitioners consider their lack of full authority to prescribe drugs to be the major impediment preventing them from delivering care efficiently (Aiken L: personal communication). In recent years, nurse practitioners have made limited progress in their efforts to remove this hurdle and other scope-of-practice restrictions. Since 2010, expanded scope-of-practice boundaries for nurse practitioners were reported in Colorado, Hawaii, Maryland, Massachusetts, North Dakota, and Vermont. The American Association of Nurse Practitioners reports that bills have been introduced this year in 10 state legislatures (in Connecticut, Illinois, Kansas, Kentucky, Massachusetts, Michigan, Minnesota, New Jersey, Nevada, and Texas) that propose expansion of the practice authority of nurse practitioners. In addition to scope-of-practice restrictions, the policies of public and private payers to varying degrees limit which services nurse practitioners are paid for, their payment rates, and whether they are designated as primary care providers and included in insurance and provider networks as independent practitioners.45 Because state-based scope-of-practice laws affect a large national workforce approximately 3 million nurses the IOM report asserted that the federal government should have a compelling interest in the regulatory environment for health care professions . . . especially that of APRNs. Specifically, the report emphasized, the FTC has a long history of targeting anticompetitive conduct in health care markets by responding to potential policies that might be viewed predominantly as guild protection rather than consumer protection. The FTC, clearly influenced by the IOM report and an increase in requests from state legislators, has accelerated its health carerelated activities since 2010. Among its actions were letters to legislators in Missouri46 and Tennessee47 asserting that nurse anesthetists can safely provide interventional management services for patients with chronic pain without physician supervision. In a more recent instance, the FTC wrote in a letter to the Connecticut House of Representatives that physician supervision of APRNs was unnecessary.48 The FTC based its opinion on the IOM report and noted that it had dismissed any contention that APRNs are less capable than doctors in delivering safe, efficient, and effective care and that decades of research had documented that fact.48 In response, Dr. Jeremy Lazarus, president of the AMA, stated that physicians have raised concerns that the physician-led model of care is being undermined by the Federal Trade Commission through its recent aggressive advocacy on behalf of the independent practice of non-physician health care professionals, such as nurse practitioners.49 Governors only rarely become heavily involved in scope-of-practice skirmishes, although they are mindful of them because they sign into law bills enacted by their state legislatures. Over the past decade, only one governor, Pennsylvania Democrat Edward Rendell, who served from 2003 to 2011, aggressively wielded his influence to persuade his state legislature to expand the scope of practice of nurse practitioners and

other nonphysician providers.50 To underscore its political symbolism, Rendell signed the measure into law at the School of Nursing of the University of Pennsylvania. Given the virtual noninvolvement of governors in scope-of-practice matters, it came as a surprise when the National Governors Association issued a report in December 2012 recommending that states consider reexamining their scope-of-practice laws as one option for increasing the number of primary care providers.7 In Virginia, after prolonged negotiations that engaged the Medical Society of Virginia and the Virginia Council of Nurse Practitioners, the state legislature unanimously enacted a compromise struck by the two organizations in March 2012.8 The law stipulates that nurse practitioners must work as part of a patient-care team led and managed by a physician, and they must adhere to scope-of-practice limits as applied to them. The law expands from four to six the number of nurse practitioners who can be supervised by a physician, and it recognizes telemedicine as a legal form of oversight when nurse practitioners practice in different locations. The boards of medicine and nursing in Virginia jointly drafted regulations implementing the law. The AMA promotes the Virginia law as a model that other states should consider, but the American Association of Nurse Practitioners believes the law places Virginia out of step with national trends. Team-based care is seen as a wave of the future, but progress has been slow because interprofessional educational opportunities are few (though increasing), training silos are many, and cultural change is difficult.51-56 The Robert Wood Johnson Foundation recognized the emerging state of the model and the controversies surrounding the IOM report and invited a dozen leaders of national physician and nurse organizations to discuss their differences. In setting the context, Dr. Risa Lavizzo-Mourey, chief executive officer (CEO) of the foundation, urged conferees to engage without using terms with charged meanings, such as `scope of practice,' `independent' and `lead' that often have us talking past each other.57 After three constructive meetings in 2011, the foundation prepared a 24-page draft document entitled Common Ground: An Agreement between Nurse and Physician Leaders on Interprofessional Collaboration for the Future of Patient Care.58The draft touched on an array of hot buttons that have divided physicians and nurses. For example, The `captain of the ship' notion . . . needs to be eliminated, focusing on the patient as the driver of care. We need to move from hierarchical leadership to situational leadership . . . A physician, nurse, social worker or other provider may take the lead in a given situation. The staff of the Robert Wood Johnson Foundation, participating nurse leaders, and several physician representatives were under the impression that all the principal attendees leaned toward support of the document but, ultimately, that proved not to be the case. In the course of the process, when principals shared the document with their national organizations for their reactions, it was leaked prematurely to the AMA, which had not been invited to the foundation's meetings, and it drew opposition from the house of delegates of the association at its 2011 midwinter meeting. After that, the AAFP, the American Osteopathic Association, and the American Academy of Pediatrics withdrew their support from the dialogue sponsored by the Robert Wood Johnson Foundation; these withdrawals led to its collapse without public notice. In describing lessons learned, Hassmiller, who directed the staff of the IOM report, said, you can get [physicians and nurses] to work together on the front lines. At the association level, there's a lot of guild protection.59 Dr. Steven Weinberger, CEO of the American College of Physicians and a participant in the foundation's discussion, said: It's a whole different conversation when you have people talking face to face. When you have people dealing in isolated organizations, the other profession can become a black box that's easy to rail against.59

Battles between national medical and nursing organizations will undoubtedly continue,60 but the larger challenge of providing coverage to millions of newly insured persons is likely to provoke outcries assuming these persons have difficulty gaining access to care and hold the potential of turning their turf wars into broader public issues that bear closer federal and state government scrutiny and accelerate private-market action. However, given the partisanship that thwarts policymaking in the nation's capital and many states, progress in restructuring delivery systems may come more rapidly at the practice level, where physicians, nurses, and other caregivers are freer to innovate and to assign tasks to persons on the basis of the full extent of their training and what makes organizational sense. Greater leadership among physicians and nurses who are prepared to challenge their guilds may also become an imperative in addressing these complex issues.61,62

A 63-year-old man was evaluated for a 6-month history of oral ulcerations. His medical history was notable for ulcerative colitis. Physical examination revealed numerous white, friable micropustules in a cobblestone pattern on labial and buccal mucosae, as well as ulcerations and hemorrhagic crusting (Panel A). A shave-biopsy specimen revealed an acanthotic epidermis, parakeratosis, exocytosis of neutrophils, and microabscesses. Pyostomatitis vegetans was diagnosed. Pyostomatitis vegetans is an oral manifestation of inflammatory bowel disease, more commonly seen in patients with ulcerative colitis. Bowel disease can precede oral lesions by years. Such lesions may also be a marker of subclinical intestinal disease. Pathogenesis is attributed to antigens that cross-react between the bowel and the skin. Treatment is aimed at controlling intestinal disease; the administration of antineutrophilic agents has also been effective. The patient was treated with dapsone, 200 mg daily, with improvement in the ulcerations within 1 week after the initiation of therapy (Panel B) and no residual oral lesions at the 1-year follow-up (Panel C).

BACKGROUND
Patients chronically infected with hepatitis C virus (HCV) genotype 2 or 3 for whom treatment with peginterferon is not an option, or who have not had a response to prior interferon treatment, currently have no approved treatment options. In phase 2 trials, regimens including the oral nucleotide polymerase inhibitor sofosbuvir have shown efficacy in patients with HCV genotype 2 or 3 infection.

METHODS
We conducted two randomized, phase 3 studies involving patients with chronic HCV genotype 2 or 3 infection. In one trial, patients for whom treatment with peginterferon was not an option received oral sofosbuvir and ribavirin (207 patients) or matching placebo (71) for 12 weeks. In a second trial, patients who had not had a response to prior interferon therapy received sofosbuvir and ribavirin for 12 weeks (103 patients) or 16 weeks (98). The primary end point was a sustained virologic response at 12 weeks after therapy.

RESULTS
Among patients for whom treatment with peginterferon was not an option, the rate of a sustained virologic response was 78% (95% confidence interval [CI], 72 to 83) with sofosbuvir and ribavirin, as compared with 0% with placebo (P<0.001). Among previously treated patients, the rate of response was 50% with 12 weeks of treatment, as compared with 73% with 16 weeks of treatment (difference, 23 percentage points; 95% CI, 35 to 11; P<0.001). In both studies, response rates were lower among patients with genotype 3 infection than among those with genotype 2 infection and, among patients with genotype 3 infection, lower

among those with cirrhosis than among those without cirrhosis. The most common adverse events were headache, fatigue, nausea, and insomnia; the overall rate of discontinuation of sofosbuvir was low (1 to 2%).

CONCLUSIONS
In patients with HCV genotype 2 or 3 infection for whom treatment with peginterferon and ribavirin was not an option, 12 or 16 weeks of treatment with sofosbuvir and ribavirin was effective. Efficacy was increased among patients with HCV genotype 2 infection and those without cirrhosis. In previously treated patients with genotype 3 infection, 16 weeks of therapy was significantly more effective than 12 weeks. (Funded by Gilead Sciences; POSITRON and FUSION ClinicalTrials.gov numbers, NCT01542788 and NCT01604850, respectively.)

BACKGROUND
In phase 2 trials, the nucleotide polymerase inhibitor sofosbuvir was effective in previously untreated patients with chronic hepatitis C virus (HCV) genotype 1, 2, or 3 infection.

METHODS
We conducted two phase 3 studies in previously untreated patients with HCV infection. In a single-group, open-label study, we administered a 12-week regimen of sofosbuvir plus peginterferon alfa-2a and ribavirin in 327 patients with HCV genotype 1, 4, 5, or 6 (of whom 98% had genotype 1 or 4). In a noninferiority trial, 499 patients with HCV genotype 2 or 3 infection were randomly assigned to receive sofosbuvir plus ribavirin for 12 weeks or peginterferon alfa-2a plus ribavirin for 24 weeks. In the two studies, the primary end point was a sustained virologic response at 12 weeks after the end of therapy.

RESULTS
In the single-group study, a sustained virologic response was reported in 90% of patients (95% confidence interval, 87 to 93). In the noninferiority trial, a sustained response was reported in 67% of patients in both the sofosbuvirribavirin group and the peginterferonribavirin group. Response rates in the sofosbuvir ribavirin group were lower among patients with genotype 3 infection than among those with genotype 2 infection (56% vs. 97%). Adverse events (including fatigue, headache, nausea, and neutropenia) were less common with sofosbuvir than with peginterferon.

CONCLUSIONS
In a single-group study of sofosbuvir combined with peginterferonribavirin, patients with predominantly genotype 1 or 4 HCV infection had a rate of sustained virologic response of 90% at 12 weeks. In a noninferiority trial, patients with genotype 2 or 3 infection who received either sofosbuvir or peginterferon with ribavirin had nearly identical rates of response (67%). Adverse events were less frequent with sofosbuvir than with peginterferon. (Funded by Gilead Sciences; FISSION and NEUTRINO ClinicalTrials.gov numbers, NCT01497366and NCT01641640, respectively.) Each year, an estimated 1.25 million pacemakers and 410,000 implantable cardioverterdefibrillators (ICDs) are implanted worldwide.1 Between 14 and 35% of patients receiving these devices require long-term oral anticoagulation therapy,2-5 and their periprocedural treatment presents a dilemma to physicians. This is particularly true for the subset of patients at moderate-to-high risk (5% per year) for thromboembolic

events.6 Current guidelines recommend interruption of oral anticoagulation therapy and the use of bridging therapy with intravenous unfractionated heparin or subcutaneous low-molecular-weight heparin around the time of surgery.6 However, there are a number of potential drawbacks to bridging with heparin in the perioperative period. This approach consumes considerable health care resources.7 Bridging with heparin also involves a short period of normal coagulability (perhaps even hypercoagulability related to the prothrombotic state of surgery) with an associated risk of thromboembolism. Finally, among patients undergoing pacemaker or ICD surgery, there is a substantial risk of device-pocket hematoma (17 to 31%) when bridging with heparin is used.8-11 Device-pocket hematomas can have serious consequences for patients, such as the need for prolonged cessation of all oral anticoagulation therapy with the attendant risk of thromboembolism,9,12 prolongation of hospitalization,13 the need for further surgery (e.g., hematoma evacuation), and an increased risk of infection.14,15 In response to these issues, some centers have started performing pacemaker and ICD surgery without interruption of anticoagulation therapy with warfarin.16,17 However, there have been limited data from clinical trials to support the safety and efficacy of this approach. Two small, randomized trials have been inconclusive.18,19 In the first of these trials, device-pocket hematoma developed in 4 of 51 patients (7.8%) in the heparin-bridging group and in 4 of 50 (8.0%) in the continued-warfarin group after implantation.19 In the second trial, only 7 patients received bridging therapy with heparin.18 We sought to resolve this dilemma with an adequately powered, randomized clinical trial.

METHODS
Study Design We conducted the Bridge or Continue Coumadin for Device Surgery Randomized Controlled Trial (BRUISE CONTROL) as a multicenter, single-blind, randomized, controlled trial. The trial was designed to determine whether a strategy of continued warfarin treatment at the time of pacemaker or ICD surgery, in patients at moderate-to-high risk for thromboembolic events, reduces the incidence of clinically significant devicepocket hematoma, as compared with the current standard of practice of bridging with heparin. Full details of the trial design have been published previously.20 The trial was designed by the steering committee (see the Supplementary Appendix, available with the full text of this article at NEJM.org). The protocol (available at NEJM.org) was approved by the research ethics board at each of the participating centers. The University of Ottawa Heart Institute Cardiovascular Research Methods Centre coordinated the study, collected the data, maintained the database, and performed all the data analyses. All the authors attest to the accuracy and completeness of the reported data, as well as the fidelity of this report to the study protocol. There was no commercial support or involvement in this trial. Patients We enrolled patients at 17 centers in Canada and at 1 center in Brazil.20 In brief, patients were eligible if they had an annual predicted risk of thromboembolism of 5% or more (see theSupplementary

Appendix),21 were taking warfarin, and required nonemergency device (pacemaker or ICD) surgery. Device
surgery included implantation of a new device, pulse-generator change, lead replacement, or pocket revision. All patients provided written informed consent. Study Procedures

Eligible patients were randomly assigned in a 1:1 ratio to continued warfarin treatment or bridging therapy with heparin. Randomization was performed with the use of sealed, opaque, serially numbered envelopes and randomly selected block sizes of four to six and was stratified according to clinical center. In the continued-warfarin group, the international normalized ratio (INR) on the day of surgery was targeted to be 3.0 or lower, except for patients with one or more mechanical valves, for whom an INR of 3.5 or less was permitted. Patients in the heparin-bridging group discontinued warfarin 5 days before the procedure and started receiving full therapeutic doses of low-molecular-weight heparin or intravenous heparin 3 days before the procedure. For patients receiving bridging therapy with low-molecular-weight heparin, the final dose was given the morning of the day before the procedure (i.e., >24 hours before the procedure). For patients receiving bridging therapy with intravenous heparin, the infusion was discontinued at least 4 hours before surgery. The administration of heparin was reinitiated 24 hours after the procedure and was continued until a therapeutic INR was achieved. Full details of the heparin-bridging protocol are provided in the Supplementary Appendix. Clopidogrel was stopped for 5 days before surgery in patients who had undergone implantation of a baremetal stent more than 1 year previously. Clopidogrel was continued in patients with more recently implanted bare-metal stents and in patients with drug-eluting stents. The timing of reinitiation of clopidogrel therapy after device surgery was at the physician's discretion. Aspirin was continued in all patients. Patients were aware of the assigned study treatment; blinding was not possible because of the very different nature of the two treatments. To ensure that the investigators were unaware of the study assignments, each center was required to identify two patient-care teams. Each team consisted of one or more research coordinators and one or more physicians. One team had knowledge of the treatment assignments and was responsible for device implantation and follow-up of programming and function but was not allowed any involvement in the evaluation for or management of a device-pocket hematoma. The second team, which had no knowledge of treatment assignments, was responsible for monitoring the surgical wound during the initial hospitalization, at 1 to 2 weeks of follow-up, and during any hospital visits or subsequent admissions and for diagnosing and making all decisions about the management of devicepocket hematomas. Patients in whom a clinically significant hematoma developed were followed until it resolved. Follow-up included monitoring for any additional complications related to the hematoma (e.g., infection). Outcome Measures The primary outcome was clinically significant device-pocket hematoma, defined as a hematoma requiring further surgery, resulting in prolongation of hospitalization, or requiring interruption of oral anticoagulation therapy. Prolongation of hospitalization was defined as extended hospitalization or rehospitalization for at least 24 hours after the index surgical procedure, primarily due to the hematoma. Interruption of anticoagulation therapy was defined as reversal or intentional withholding of oral anticoagulation treatment because of a device-pocket hematoma, resulting in subtherapeutic anticoagulation for at least 24 hours. Secondary outcomes included each component of the primary outcome, the composite of all other major perioperative bleeding events (hemothorax, cardiac tamponade, or clinically significant pericardial effusion), thromboembolic events (transient ischemic attack, stroke, deep-vein thrombosis, pulmonary embolism, systemic embolism, or valve thrombosis), death from any cause, quality of life, perioperative pain, and

patient satisfaction. Details of the assessments of quality of life, pain, and patient satisfaction are provided in the Supplementary Appendix. Statistical Analysis We calculated that a sample size of 984 patients would provide 80% power to detect a 30% reduction in the relative risk of the primary outcome in the continued-warfarin group, with the use of a two-sided alpha level of 0.05. We did not expect substantial rates of noncompliance or loss to follow-up. Two interim analyses were planned, when 33% and 66% of the patients had completed follow-up, with review by an independent data and safety monitoring board. We used a group-sequential method with an O'BrienFleming boundary, with P values of 0.0002 and 0.0119 for the first and second interim analyses, respectively. Descriptive statistics were used for all baseline variables, with means and standard deviations for normally distributed variables, medians and interquartile ranges for nonnormally distributed variables, and rates and proportions for discrete outcomes in each treatment group. Primary and secondary outcomes were compared between treatment groups with the use of the chi-square test. Prespecified subgroup analyses included comparisons of outcomes according to whether patients were taking clopidogrel, whether patients were taking any antiplatelet agent, and whether the planned surgery was for implantation of a new device, a pulse-generator change alone, or a pulse-generator change plus an additional procedure. Analyses were conducted with the use of SAS software, version 9.2 (SAS Institute).

RESULTS
Study Patients Data on 668 patients were reviewed by the data and safety monitoring board at the second prespecified interim analysis, on February 27, 2013, at which time the board recommended termination of the study. All patients who had undergone both randomization and device surgery before this date were followed until study completion. We therefore report data on 681 patients enrolled between October 2009 and February

2013. Details of trial enrollment and follow-up are shown in Figure 1FIGURE 1

Trial

Enrollment and Follow-up.. The baseline clinical and demographic characteristics of the patients were similar

in the two groups (Table 1TABLE 1 Characteristics of the Patients at Baseline.). Device Surgery and Perioperative Anticoagulation Preoperative bridging therapy was performed with the use of low-molecular-weight heparin (in 89.0% of patients), intravenous heparin (in 10.7%), or both (in 0.3%). Postoperative bridging therapy was performed with the use of low-molecular-weight heparin (in 82.2% of patients), intravenous heparin (in 15.9%), or both (in 1.9%). The median INR on the day of surgery was 1.2 (interquartile range, 1.1 to 1.3) in the heparinbridging group and 2.3 (interquartile range, 2.0 to 2.6) in the continued-warfarin group (P<0.001). There

were no significant between-group differences in any other perioperative variables (Table 2TABLE 2

Operative Details.).

Surgery was postponed in eight patients in the continued-warfarin group because of a supratherapeutic INR on the day of surgery (mean [SD] INR, 3.90.4). In the heparin-bridging group, surgery was postponed in three patients (P=0.27); two patients had supratherapeutic INRs of 1.9 and 2.8, and bridging therapy in one patient had not been discontinued according to protocol. Primary Outcome The primary outcome occurred in 12 of 343 patients (3.5%) in the continued-warfarin group as compared with 54 of 338 (16.0%) in the heparin-bridging group (relative risk, 0.19; 95% confidence interval (CI), 0.10 to 0.36; P<0.001). There were significant differences in each of the three components of the primary

outcome (Table 3TABLE 3

Primary and Secondary Outcomes.). Treatment effects were

consistent in each of seven subgroups (Figure 2FIGURE 2

Clinically Significant Device-Pocket Hematoma.).

Subgroup Analyses of

Secondary Outcomes Secondary outcomes are shown in Table 3. There were no embolic events in the heparin-bridging group. Two patients in the continued-warfarin group had embolic events; both patients had nonvalvular atrial fibrillation and a high risk of stroke as determined at enrollment according to the CHADS 2 score (an index of the risk of stroke among patients with atrial fibrillation, with scores ranging from 0 to 6 and higher scores indicating a greater risk of stroke). A stroke in the right occipital lobe occurred 2 days after surgery in an 89year-old woman with a CHADS2 score of 5 and an INR of 1.2 on the day of surgery. A transient ischemic attack occurred 2 days after surgery in an 88-year-old woman with a CHADS2 score of 4 and an INR of 1.0 on the day of surgery. In both patients, the subtherapeutic INR was not intentional. There was one episode of cardiac tamponade requiring pericardiocentesis in the heparin-bridging group. Six patients in the heparin-bridging group (1.8%) and two in the continued-warfarin group (0.6%) had infections related to the device system (P=0.17). In all eight patients, the infection necessitated complete system extraction. As compared with patients in the heparin-bridging group, those in the continued-warfarin group reported greater satisfaction with the management of their perioperative anticoagulation therapy, but there were no significant differences in quality of life or perioperative pain scores (Table S1 in the Supplementary Appendix). Deaths

There were four deaths, all occurring in the continued-warfarin group (P=0.12). Three patients died before surgery: one patient died suddenly from a cardiac cause while awaiting elective surgery for a pulsegenerator change, one patient died after metastatic pancreatic cancer was diagnosed and the device implantation was canceled, and one patient died from intraperitoneal hemorrhage after paracentesis (INR, 1.3). The fourth patient died from end-stage heart failure 10 days after surgery. Clinically Significant Hematoma Three risk factors had independent predictive value for the development of clinically significant devicepocket hematoma: randomized assignment to continued warfarin (relative risk, 0.16; 95% CI, 0.08 to 0.32; P<0.001), diabetes mellitus (relative risk, 0.48; 95% CI, 0.26 to 0.86; P=0.01), and use of aspirin (relative risk, 2.04; 95% CI, 1.19 to 3.48; P=0.01) (Table S4 and S5 in theSupplementary Appendix). Patients with hematomas had significant increases in perioperative pain and significant decreases in quality of life. Details of follow-up data for patients with hematomas are provided in the Supplementary Appendix.

DISCUSSION
In this large, randomized trial, we evaluated the safety of performing pacemaker or ICD surgery without interruption of warfarin therapy in patients requiring oral anticoagulation therapy. We found that this strategy is associated with a significantly lower rate of device-pocket hematoma, as compared with bridging therapy with heparin (3.5% vs. 16.0%). We also found that continued warfarin therapy, with a median INR of 2.3 (interquartile range, 2.0 to 2.6), was not associated with any major perioperative bleeding events and was associated with greater patient satisfaction. These results suggest that continuation of warfarin during pacemaker or ICD surgery may be preferable to bridging therapy with heparin, at least for patients like those enrolled in our trial. The significantly lower rate of device-pocket hematoma that we observed with continued warfarin may seem counterintuitive. One explanation that has been proposed is the concept of an anticoagulant stress test.9 That is, if patients undergo surgery while receiving full-dose anticoagulation therapy, any excessive bleeding will be detectable and appropriately managed while the wound is still open. In contrast, if bridging therapy with heparin is used, such bleeding may be apparent only when full-dose anticoagulation therapy is resumed postoperatively.9 Our results are consistent with observations on bridging therapy in other situations. Siegal et al. 22recently conducted a meta-analysis of the safety and efficacy of periprocedural bridging therapy, which included more than 12,000 patients in 34 studies, with only one randomized trial. The comparison groups in these studies included mostly patients in whom oral anticoagulation therapy was discontinued without bridging, with smaller numbers of patients in whom oral anticoagulation therapy was continued during surgery. The authors concluded that bridging with heparin leads to a risk of overall bleeding that is 5 times as high, and a risk of major bleeding that is 3.6 times as high, as the respective risks associated with no bridging therapy. The risk of thromboembolic events did not differ significantly between the two treatment strategies. 22 We specifically included patients with an annual risk of thromboembolic events of more than 5%, for whom complete discontinuation of anticoagulation therapy at the time of surgery might have been too risky. The findings of our trial are not directly relevant to patients with a lower risk of thromboembolic events (<5%), and it is possible that such patients may not require any anticoagulation or bridging therapy during the periprocedural period. Additional data from large, randomized trials are needed to better define the role of periprocedural bridging therapy with heparin.

Guidelines suggest that the continuation of warfarin at the time of minor dental, dermatologic, or ophthalmologic procedures is associated with an acceptable risk of bleeding. 6,21 Although not directly relevant, the results of our study are consistent with this recommendation, particularly since the bleeding risk is low with these other procedures, whereas the risk is increased with pacemaker or ICD surgery. 6 Physicians have begun to explore performing other procedures and operations without interruption of warfarin therapy. Case series have shown low rates of bleeding complications with coronary angiography and stenting,23,24 minor head and neck surgery,25 urologic procedures,26colonoscopic polypectomy,27 hand surgery,28 vascular surgery,29 joint injections and aspirations,30and hip and knee replacements.29 However, additional randomized, controlled trials are needed in these areas. It should also be recognized that a strategy of continued warfarin is unlikely to be considered in major abdominal, cardiothoracic, or neurologic surgery. Three oral anticoagulant agents dabigatran, rivaroxaban, and apixaban have been approved within the past few years for the prevention of stroke in patients with atrial fibrillation.31-33 These agents have short half-lives, with maximal anticoagulant effects observed soon after oral intake and reduction of the effects soon after discontinuation. Whether it is better for patients to undergo surgery without interruption of these agents or with temporary cessation is currently unclear. The results of our study cannot be applied to patients receiving these agents. One limitation of our trial is the subjectivity of the primary end point and the possibility that on occasion the team that was initially unaware of the treatment assignment became aware of the assignment and allowed biases to affect the assessment of primary end-point events. The most obvious potential situation for unblinding was among patients who were prescribed postoperative intravenous heparin. However, this treatment was used in only 17.8% of the patients, and the incidence of hematoma was similar among patients treated with postoperative intravenous heparin (16.1%) and those treated with postoperative lowmolecular-weight heparin (16.6%). There is additional reassurance about the veracity of the blinding from the objective data showing that patients with hematomas had significant increases in perioperative pain and significant decreases in quality of life. In conclusion, we investigated two approaches to performing pacemaker or ICD surgery in patients requiring long-term oral anticoagulation therapy. Patients were randomly assigned to undergo the planned operation with bridging anticoagulation therapy with heparin or to undergo the surgery without interruption of warfarin therapy. Patients who underwent surgery without interruption of warfarin therapy had a markedly reduced incidence of clinically significant device-pocket hematoma, as compared with those who received bridging therapy with heparin.
Supported by a grant from the Canadian Institutes of Health Research (CIHR), a CIHR Clinician-Scientist Award (to Dr. Essebag), and a grant from the University of Ottawa Heart Institute Academic Medical Organization Alternate Funding Program (funded by the Ministry of Health and Long-Term Care of Ontario). Disclosure forms provided by the authors are available with the full text of this article at NEJM.org. This article was published on May 9, 2013, at NEJM.org.

BACKGROUND
The U.S. health care system is at a critical juncture in health care workforce planning. The nation has a shortage of primary care physicians. Policy analysts have proposed expanding the supply and scope of practice of nurse practitioners to address increased demand for primary care providers. These proposals are controversial.

METHODS
From November 23, 2011, to April 9, 2012, we conducted a national postal-mail survey of 972 clinicians (505 physicians and 467 nurse practitioners) in primary care practice. Questionnaire domains included scope of work, practice characteristics, and attitudes about the effect of expanding the role of nurse practitioners in primary care. The response rate was 61.2%.

RESULTS
Physicians reported working longer hours, seeing more patients, and earning higher incomes than did nurse practitioners. A total of 80.9% of nurse practitioners reported working in a practice with a physician, as compared with 41.4% of physicians who reported working with a nurse practitioner. Nurse practitioners were more likely than physicians to believe that they should lead medical homes, be allowed hospital admitting privileges, and be paid equally for the same clinical services. When asked whether they agreed with the statement that physicians provide a higher-quality examination and consultation than do nurse practitioners during the same type of primary care visit, 66.1% of physicians agreed and 75.3% of nurse practitioners disagreed.

CONCLUSIONS
Current policy recommendations that are aimed at expanding the supply and scope of practice of primary care nurse practitioners are controversial. Physicians and nurse practitioners do not agree about their respective roles in the delivery of primary care. (Funded by the Gordon and Betty Moore Foundation and others.)

Only 20 years after the discovery of the hepatitis C virus, a cure is now likely for most people with chronic infection. This review considers current therapy and the present landscape of drug development for hepatitis C.