Intravenous immunoglobulin therapy has been proposed as an adjuvant treatment for sepsis. Yet, its benefit remains unclear, and its use is not currently recommended.

Venous thromboembolism is a common condition affecting 7.1 persons per 10,000 person-years among community residents. Incidence rates for venous thromboembolism are higher in men and African Americans and increase substantially with age. It is critical to treat deep venous thrombosis at an early stage to avoid development of further complications, such as pulmonary embolism or recurrent deep venous thrombosis. The target audience for this guideline is all clinicians caring for patients who have been given a diagnosis of deep venous thrombosis or pulmonary embolism. The target patient population is patients receiving a diagnosis of pulmonary embolism or lower-extremity deep venous thrombosis.

New treatments are available for treatment of venous thromboembolism.

The prevalence, efficacy, and risk for addiction for persons receiving opioids for chronic back pain are unclear.

Human growth hormone (GH) is widely used as an antiaging therapy, although its use for this purpose has not been approved by the U.S. Food and Drug Administration and its distribution as an antiaging agent is illegal in the United States.

Reversible cerebral vasoconstriction syndromes (RCVS) comprise a group of diverse conditions, all characterized by reversible multifocal narrowing of the cerebral arteries heralded by sudden (thunderclap), severe headaches with or without associated neurologic deficits. Reversible cerebral vasoconstriction syndromes are clinically important because they affect young persons and can be complicated by ischemic or hemorrhagic strokes. The differential diagnosis of RCVS includes conditions associated with thunderclap headache and conditions that cause irreversible or progressive cerebral artery narrowing, such as intracranial atherosclerosis and cerebral vasculitis. Misdiagnosis as primary cerebral vasculitis and aneurysmal subarachnoid hemorrhage is common because of overlapping clinical and angiographic features. However, unlike these more ominous conditions, RCVS is usually self-limited: Resolution of headaches and vasoconstriction occurs over a period of days to weeks. In this review, we describe our current understanding of RCVS; summarize its key clinical, laboratory, and imaging features; and discuss strategies for diagnostic evaluation and treatment.

Rituximab, a monoclonal anti-CD20 antibody, is increasingly used to treat idiopathic thrombocytopenic purpura (ITP).

It is nearly impossible to be a practicing internist in the United States and have a day of clinical work pass without encountering at least 1 patient with type 2 diabetes. Currently, over 20 million Americans and over 150 million worldwide have type 2 diabetes. Models estimate that this number will nearly double by the year 2050 so that about one third of adult Americans will have the disease. This In the Clinic feature includes answers to these and other practical, clinical questions... What are the diagnostic criteria for type 2 diabetes in nonpregnant adults? Should we screen for type 2 diabetes? Can we prevent type 2 diabetes? What should the initial evaluation of patients with newly diagnosed type 2 diabetes include? What measures do U.S. stakeholders use to evaluate the quality of care for patients with type 2 diabetes? Only ACP members and individual subscribers can access the electronic features of In the Clinic. Non-subscribers who wish to access this issue of In the Clinic can elect "Pay for View." Subscribers can receive 1.5 category 1 CME credits by completing the CME quiz that accompanies this issue of In the Clinic. The content of In the Clinic is drawn from the clinical information and education resources of the American College of Physicians (ACP), including PIER (Physicians' Information and Education Resource) and MKSAP (Medical Knowledge and Self Assessment Program). Annals of Internal Medicine editors develop In the Clinic from these primary sources in collaboration with the ACP's Medical Education and Publishing division and with assistance of science writers and physician writers. Editorial consultants from PIER and MKSAP provide expert review of the content. Readers who are interested in these primary resources for more detail can consult www.acponline.org, http://pier.acponline.org, and other resources referenced within each issue of In the Clinic.

Chronic myeloid leukemia (CML) was the first human malignant disease to be linked to a single, acquired genetic abnormality. Identification of the BCR-ABL kinase fusion protein and its central role in the pathogenesis of CML provided new opportunities to develop rational molecular targeted therapies. This review provides an update on the underlying pathophysiologies of disease progression and imatinib mesylate resistance, leading to the development of new targeted tyrosine kinase inhibitors for managing CML. Imatinib, a selective inhibitor of BCR-ABL, represents a major success in the era of target-directed cancer chemotherapy. However, patients with advanced CML have been less sensitive to therapy and responses have been short. In addition, treatment resistance is an emerging problem at all disease stages. Insight into factors involved in imatinib resistance and disease progression has highlighted a role for such BCR-ABL-dependent factors as amplification and overexpression of the BCR-ABL gene and the emergence of mutant isoforms of BCR-ABL. However, BCR-ABL-independent factors, including leukemogenic pathways involving kinases other than BCR-ABL, also play a part. In light of the limitations of imatinib against these factors, newer tyrosine kinase inhibitors, including dasatinib (a multitargeted kinase inhibitor of BCR-ABL and Src family kinases) and nilotinib (AMN107, a selective BCR-ABL inhibitor), may provide promising treatment options for patients with CML.

Antibiotic-associated diarrhea and colitis were well established soon after antibiotics became available. Early work implicated Staphylococcus aureus, but in 1978 Clostridium difficile became the established pathogen in the vast majority of cases. In the first 5 years (1978 through 1983), the most common cause was clindamycin, the standard diagnostic test was the cytotoxin assay, and standard management was to withdraw the implicated antibiotic and treat with oral vancomycin. Most patients responded well, but 25% relapsed when vancomycin was withdrawn. During the next 20 years (1983 through 2003), the most commonly implicated antibiotics were the cephalosporins, which reflected the rates of use; the enzyme immunoassay replaced the cytotoxin assay because of speed of results and technical ease of performance; and metronidazole replaced vancomycin as standard treatment, and principles of containment hospitals became infection control and antibiotic control. During the recent past (2003 to 2006), C. difficile has been more frequent, more severe, more refractory to standard therapy, and more likely to relapse. This pattern is widly distributed in the United States, Canada, and Europe and is now attributed to a new strain of C. difficile designated BI, NAP1, or ribotype 027 (which are synonymous terms). This strain appears more virulent, possibly because of production of large amounts of toxins, and fluoroquinolones are now major inducing agents along with cephalosporins, which presumably reflects newly acquired in vitro resistance and escalating rates of use. The recent experience does not change principles of management of the individual patient, but it does serve to emphasize the need for better diagnostics, early recognition, improved methods to manage severe disease and relapsing disease, and greater attention to infection control and antibiotic restraint.

The outcome of drug therapy is often unpredictable, ranging from beneficial effects to lack of efficacy to serious adverse effects. Variations in single genes are 1 well-recognized cause of such unpredictability, defining the field of pharmacogenetics (see Glossary). Such variations may involve genes controlling drug metabolism, drug transport, disease susceptibility, or drug targets. The sequencing of the human genome and the cataloguing of variants across human genomes are the enabling resources for the nascent field of pharmacogenomics (see Glossary), which tests the idea that genomic variability underlies variability in drug responses. However, there are many challenges that must be overcome to apply rapidly accumulating genomic information to understand variable drug responses, including defining candidate genes and pathways; relating disease genes to drug response genes; precisely defining drug response phenotypes; and addressing analytic, ethical, and technological issues involved in generation and management of large drug response data sets. Overcoming these challenges holds the promise of improving new drug development and ultimately individualizing the selection of appropriate drugs and dosages for individual patients.

Value-based purchasing, or pay-for-performance, is a major emerging theme in U.S. health care. Forces enhancing adoption of pay-for-performance programs include continued increases in medical costs beyond overall economic growth, a body of evidence that the quality of health care provided to patients is not directly related to the volume of services received, increasing evidence to serve as a basis for the development of standards against which to measure clinical performance, and increasing acceptance by physician organizations and individual practitioners of the rationale underlying these efforts. In this context, employers, government payers, and health plans are establishing a wide variety of pay-for-performance programs. This article reviews the critical design features of such efforts, describes the current types of programs on offer, and comments on the implications of this emerging movement for the future of health care in the United States.

Long-acting beta-agonists are a pillar of therapy for many patients with asthma because they are the preferred add-on therapy to inhaled corticosteroids. However, a recent meta-analysis documented a substantial increase in severe exacerbations requiring hospital admission and life-threatening asthma exacerbations in patients treated with long-acting beta-agonists. A careful evaluation of this meta-analysis raises several concerns about its applicability to current practice. Pivotal trials evaluating the benefit of adding long-acting beta-agonists to inhaled corticosteroids were not included. The authors of the current paper call for physicians to continue their usual practice of using long-acting beta-agonists as adjunctive therapy, as well as for an independent meta-analysis of individual patients using inhaled corticosteroids and long-acting beta-agonists concomitantly.

Between the 1950s and 1980s, many scientists focused on the process by which the genetic code is translated into proteome. However, little attention was devoted to the mechanism responsible for protein degradation. When researchers discovered the organelle lysosome, they assumed that cellular proteins were degraded within it. However, several independent lines of evidence strongly suggested that intracellular proteolysis was largely nonlysosomal. The discovery of the ubiquitin proteasome system (UPS) resolved this enigma. It is now recognized that degradation of intracellular proteins by the UPS is involved in the regulation of a broad array of cellular processes, including cell-cycle division; DNA repair, growth, and differentiation; quality control; and regulation of membrane receptors and ion channels. Not surprisingly, aberrations in the system have been implicated in the pathogenesis of numerous human diseases, and it seems that pharmacologic manipulation of the UPS might alter the outcome of many diseases, especially malignant conditions and possibly neurodegenerative and chronic inflammatory diseases. These findings have led to increasing efforts to develop mechanism-based drugs that modulate UPS activity, one of which is already on the market. In the near future, one can expect to see the development of new, potent, and highly specific drugs that target the degradation pathways of a single or a few proteins without affecting other proteins.

Injection insulin therapy is not readily accepted by patients and many health care providers; therefore, less invasive options for insulin therapy are desirable.