Annual Review of Medicine - Volume 63, 2012

Perturbations in the normal functions of the endoplasmic reticulum (ER) trigger a signaling network that coordinates adaptive and apoptotic responses. There is accumulating evidence implicating prolonged ER stress in the development and progression of many diseases, including neurodegeneration, atherosclerosis, type 2 diabetes, liver disease, and cancer. With the improved understanding of the underlying molecular mechanisms, therapeutic interventions that target the ER stress response would be potential strategies to treat various diseases driven by prolonged ER stress.

There is controversy concerning the role of sugar in the epidemics of obesity and metabolic syndrome. There is less controversy concerning the effects of fructose on components of metabolic syndrome; consumption of fructose has been shown to increase visceral adipose deposition and de novo lipogenesis (DNL), produce dyslipidemia, and decrease insulin sensitivity in older, overweight/obese subjects. This review examines the potential mechanisms of these effects of fructose and considers whether these mechanisms are relevant to the effects of consuming sucrose or high-fructose corn syrup. Evidence demonstrating that the commonly consumed sugars increase visceral adipose deposition, DNL, and insulin insensitivity is limited or inconclusive. Evidence that sugar consumption promotes development of an unfavorable lipid profile is strong and suggests that the upper added sugar consumption limit of 25% of energy or less, suggested in the Report of the Dietary Guidelines Advisory Committee on the Dietary Guidelines for Americans 2010, may merit re-evaluation.

Vaccines are the most powerful public health tools mankind has created, but malaria parasites are bigger, more complicated, and wilier than the viruses and bacteria that have been conquered or controlled with vaccines. Despite decades of research toward a vaccine for malaria, this goal has remained elusive. Nevertheless, recent advances justify optimism that a licensed malaria vaccine is within reach. A subunit recombinant protein vaccine that affords in the neighborhood of 50% protective efficacy against clinical malaria is in the late stages of clinical evaluation in Africa. Incremental improvements on this successful vaccine are possible and worth pursuing, but the best hope for a highly efficacious malaria vaccine that would improve prospects for malaria eradication may lie with the use of attenuated whole parasites and powerful immune-boosting adjuvants.

Healthcare-associated infections (HAIs) cause significant morbidity and mortality. Recognition of the burden, cost, and preventability of HAIs has resulted in new initiatives to encourage adherence to recommended infection prevention practices and new research to better understand the pathogenesis of HAIs and to develop novel approaches to prevention. Although substantial progress in HAI prevention has been made over the past decade, many opportunities for improvement remain and new challenges continue to arise. Optimal protection of patients from the harms associated with HAIs will require not only allocation of adequate financial resources and additional scientific research, but also a strong commitment to excellence among all healthcare providers, including consistent use of proven prevention practices and appropriate use of antimicrobial agents. Although it is a daunting task, there has never been a better opportunity for the healthcare system to make the changes necessary to achieve the goal of elimination of HAIs.

For the first time since the discovery of the hepatitis C virus (HCV), therapeutic options for hepatitis C have expanded. Several agents directly effective against HCV are now in development, including both direct-acting antiviral agents (DAAs) and host cofactor inhibitors. DAAs have been developed to inhibit several HCV proteins, including the NS3/4A serine protease, the NS5B RNA polymerase, NS5A, and NS4B. Host cofactor inhibitors include, but are not limited to, cyclophilin inhibitors, miR122 antagonists, and statins. Development of these agents represents a major advance in HCV therapeutics. This review provides a guide to HCV drugs in various stages of development, including an introduction to their mechanism of action, state of clinical development, efficacy, and side effects.

Concepts of multiple sclerosis (MS) have shifted from the traditional view of a T cell–mediated, demyelinating disease of the white matter to include a broad range of immunopathogenic mechanisms, axonal damage, and widespread gray matter pathology. The cause of MS remains unknown, but recent epidemiological work has focused on genetic factors; environmental factors such as vitamin D, sunlight, and Epstein-Barr virus; and the controversial theory of chronic cerebrospinal venous insufficiency. Revised criteria facilitate making the diagnosis of MS. Emerging therapies are rapidly expanding treatment options, including both parenterally administered and oral medications. Strategies to preserve tissue, promote repair, and restore function are under development, and it is anticipated that they will provide better options for patients with progressive disease.

The post–September 11, 2001 wars in and around Afghanistan and Iraq have increased awareness of traumatic brain injury (TBI), particularly blast-induced mild TBI. This article provides an overview of TBI and its neuropsychiatric sequelae in U.S. war veterans who participated in the current operations in and around Afghanistan and Iraq, with particular emphasis on blast-related mild TBI. Psychiatric disorders, particularly posttraumatic stress disorder, pain, and sensory impairments are prevalent in war veterans with TBI. Research is needed to more definitively characterize the epidemiology of TBI-related functional difficulties, the effects of blasts compared with other mechanisms of injury, recovery trajectories, and treatment outcomes in this population.

Eosinophilic esophagitis (EoE) now represents a commonly recognized disorder among both pediatric and adult patients presenting to allergy and gastroenterology clinics throughout the world. The consequences of this localized and eosinophil-predominant inflammation of the esophagus can have an outsized and profound systemic and emotional impact for patients and their families. Unlike gastroesophageal reflux disease (GERD), whose symptoms closely overlap with those of EoE, EoE represents a primarily antigen-driven disorder whose symptoms and pathology are therapeutically mitigated with either long-term dietary control or chronic steroid therapies, rather than the acid-suppressive medications that are the mainstay of GERD treatment. Beyond the dissimilarities in their responses to treatment, these disorders are distinct in their gene expression profiles, heredity, genetic underpinning, and linkage with atopy. The antigen-driven nature of EoE has been reinforced by the remarkable impact of therapies utilizing elemental formulas to control the disease as well as a number of reports linking aeroallergens to seasonal worsening of disease.

In 2020, the United States may face shortages of 45,400 primary care physicians and 46,100 medical specialists—a total of 91,500 too few doctors. Unfortunately, health workforce shortages like these are being advanced as cause for repealing or “defunding” the Affordable Care Act (ACA). The extension of health insurance coverage to millions of Americans is a critical first step toward a healthier America. It would be a national failure to leave millions of Americans without health insurance coverage because they will generate additional demand. Rather, the solution is to find ways to meet that demand. Workforce projections utilizing real data and carefully formulated assumptions to assess how and why supply and demand change over time can greatly assist policy makers in finding those solutions. With implementation of the ACA under way, it is time to understand what lessons such projections can teach, and to begin to heed those lessons.

Medical errors account for ∼98,000 deaths per year in the United States. They increase disability and costs and decrease confidence in the health care system. We review several important types of medical errors and adverse events. We discuss medication errors, healthcare-acquired infections, falls, handoff errors, diagnostic errors, and surgical errors. We describe the impact of these errors, review causes and contributing factors, and provide an overview of strategies to reduce these events. We also discuss teamwork/safety culture, an important aspect in reducing medical errors.

Relationships between physicians and industry are prevalent in medical education, clinical practice, and research, as well as at the level of medical institutions. These relationships can be valuable for the advancement of medicine but have also received increased scrutiny in recent years because they create conflicts of interest that pose a risk of biasing the judgments of physicians. Responses to these conflicts of interest by medical institutions, journals, and governments have utilized four main tools: education, disclosure, management, and prohibition. Each of the four has its advantages and drawbacks. Medicine faces the challenge of tailoring the use of these tools to minimize the risk of bias while allowing useful medical–industry collaborations to proceed. Viewing the dilemmas created by physicians' relationships with industry as a version of the principal–agent problem, which is much discussed by economists, may help in developing creative approaches to these issues.

Healthcare information, and to some extent patient management, is progressing toward a wireless digital future. This change is driven partly by a desire to improve the current state of medicine using new technologies, partly by supply-and-demand economics, and partly by the utility of wireless devices. Wired technology can be cumbersome for patient monitoring and can restrict the behavior of the monitored patients, introducing bias or artifacts. However, wireless technologies, while mitigating some of these issues, have introduced new problems such as data dropout and “information overload” for the clinical team. This review provides an overview of current wireless technology used for patient monitoring and disease management. We identify some of the major related issues and describe some existing and possible solutions. In particular, we discuss the rapidly evolving fields of telemedicine and mHealth in the context of increasingly resource-constrained healthcare systems.

Measurements of health care spending and outcomes in a geographic area and comparisons of one area to another have been used to make observations about health delivery systems and guide health care policy. Medicare claims files are a ready source of data about health care utilization and have served as the basis for a large number of studies in the United States. If ecologic studies are to accurately reflect local practices, potential variables must be accounted for. In the United States, differences in disease burden and socioeconomic factors are important variables affecting health care spending and outcomes. The assertion that regional variation in Medicare spending in the last two years of life is indicative of widespread waste in the U.S. health care system became a controversial part of the health care reform debate in 2009–2010.

Deep brain stimulation (DBS) has virtually replaced ablative neurosurgery for use in medication-refractory movement disorders. DBS is now being studied in severe psychiatric conditions, such as treatment-resistant depression (TRD) and intractable obsessive-compulsive disorder (OCD). Effects of DBS have been reported in ∼100 cases of OCD and ∼50 cases of TRD for seven (five common) anatomic targets. Although these published reports differ with respect to study design and methodology, the overall response rate appears to exceed 50% in OCD for some DBS targets. In TRD, >50% of patients responded during acute and long-term bilateral electrical stimulation in a different target. DBS was generally well tolerated in both OCD and TRD, but some unique, target- and stimulation-specific adverse effects were observed (e.g., hypomania). Further research is needed to test the efficacy and safety of DBS in psychiatric disorders, compare targets, and identify predictors of response.

Knowledge of normal male reproductive function and familiarity with the diagnostic evaluation and treatment of male subfertility is beneficial for most physicians. Male subfertility is often correctable, may be genetically transmissible, and may be associated with occult health-threatening conditions. Herein we present an overview of male reproductive medicine, which has been revolutionized in the past two decades by dramatic scientific and therapeutic advances. The development of intracytoplasmic sperm injection and its successful application to sperm retrieved from the epididymis or testis have made biological paternity possible in men previously considered sterile. Microsurgical techniques for vasal-epididymal reconstruction and sperm retrieval have been refined. Novel tests of semen quality have been developed. Medical therapies to improve sperm production, such as estrogen receptor modulation and aromatase inhibition, have been used increasingly in clinical practice. Finally, associations between male subfertility and a spectrum of health-threatening conditions have been recognized.