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- Volume 69, 2018
Annual Review of Medicine - Volume 69, 2018
Volume 69, 2018
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Precision Medicine: Functional Advancements
Vol. 69 (2018), pp. 1–18More LessPrecision medicine was conceptualized on the strength of genomic sequence analysis. High-throughput functional metrics have enhanced sequence interpretation and clinical precision. These technologies include metabolomics, magnetic resonance imaging, and I rhythm (cardiac monitoring), among others. These technologies are discussed and placed in clinical context for the medical specialties of internal medicine, pediatrics, obstetrics, and gynecology. Publications in these fields support the concept of a higher level of precision in identifying disease risk. Precise disease risk identification has the potential to enable intervention with greater specificity, resulting in disease prevention—an important goal of precision medicine.
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Refinement of the Affordable Care Act
Vol. 69 (2018), pp. 19–28More LessRegardless of what legislation the federal government adopts to address health insurance coverage for nonelderly Americans, private insurance will likely play a major role. This article begins by listing some of the major reasons critics dislike the Affordable Care Act (ACA), then discusses the validity of these concerns from an economics perspective. Criticisms of the ACA include the increased role of government in health care, the ACA's implicit income redistribution, and concern about high and rising insurance premiums. Suggestions for refining the ACA and its market-based insurance system are then offered, with the goals of lowering insurance premiums, improving coverage rates, and/or addressing the concerns of ACA critics. Americans favor the increase in insurance coverage that has occurred under the ACA. In order to sustain this level of coverage, steps to lower Marketplace premiums through a variety of strategies affecting potential enrollees, insurers, and healthcare providers are offered.
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Refinement of the Affordable Care Act: A Progressive Perspective
Vol. 69 (2018), pp. 29–39More LessThe Affordable Care Act (ACA) was the most significant expansion of health coverage since Medicare and Medicaid were enacted. The law resulted in approximately 13–20 million uninsured persons gaining coverage. Despite these gains, the ACA has numerous shortcomings. For progressives, the ACA was a unique opportunity to provide access to high-quality, comprehensive, equitable health coverage to all persons living in the United States. Using this perspective as our framework, in this review we highlight some of the limitations of the ACA and potential areas for refinement. We conclude that the ACA fell far short of the goal of achieving universal coverage and that the coverage made available through the ACA was not equitable. In addition, the ACA expanded coverage by building onto a highly fragmented, inefficient, and costly health system. Thus, it did little to control health costs. A more fiscally prudent approach would have been built upon more successful existing programs, such as a Medicare for All.
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The Affordable Care Act: What's Next?
Vol. 69 (2018), pp. 41–52More LessThe postelection efforts to repeal, replace, or modify the Affordable Care Act (ACA) suggest that the debate over healthcare coverage will remain contentious, particularly because of the high and rising cost of health care. Feasible, potentially bipartisan approaches to improving access to coverage should emphasize reforming health care to achieve higher quality at a lower cost. In the individual market, where many enrollees face limited options and rising premiums, a combination of high-risk pools, reinsurance, and risk adjustment could improve coverage options while encouraging innovations in care for the highest-risk patients. State Medicaid programs, which are increasingly important sources of coverage but are crowding out other important budget priorities that affect population health, could achieve better results through federal reforms that provide more flexibility for states alongside greater emphasis on achieving better outcomes. Accelerating payment reforms and other policy changes to encourage more innovative and efficient care delivery models, along with developing better evidence on successful models, can also improve the prospects for coverage reform.
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Atrial Fibrillation Ablation
Vol. 69 (2018), pp. 53–63More LessThe prevalence of atrial fibrillation (AF) has risen significantly over the past two decades. Catheter ablation is an increasingly utilized treatment strategy and has evolved significantly over the same time period. Successful ablation improves patient symptoms, reduces stroke risk, and can preserve or improve cardiac function. Recurrences following ablation can occur, particularly in patients with persistent AF. Procedural efficacy can best be improved through continued advancements in ablation technology and strategy, better understanding of the mechanisms of AF initiation and perpetuation, and rigorous integration of ablation into a multidisciplinary AF management approach.
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Heart Failure with Preserved Ejection Fraction
Vol. 69 (2018), pp. 65–79More LessHeart failure (HF) is a clinical syndrome of diverse etiologies and can be associated with preserved, reduced, or mid-range ejection fraction (EF). In the community, heart failure with preserved ejection fraction (HFpEF) is emerging as the most common form of HF. There remains considerable uncertainty regarding its pathogenesis, diagnosis, and optimal therapeutic approach. Hypotheses have been advanced to explain the underlying pathophysiology responsible for HFpEF, but to date, no specific therapy based on these hypotheses has been proven to improve outcomes in HFpEF. We provide a clinically focused review of the epidemiology, clinical presentation, diagnostic approach, pathophysiology, and treatment of HFpEF.
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Impact of the SPRINT Trial on Hypertension Management
Lama Ghazi, and Suzanne OparilVol. 69 (2018), pp. 81–95More LessThe Systolic Blood Pressure Intervention Trial is the first large prospective randomized controlled trial to demonstrate the benefit of an intensive systolic blood pressure (SBP) treatment target (<120 mm Hg) compared to a standard target (<140 mm Hg) in reducing cardiovascular morbidity and mortality and all-cause mortality in high-risk hypertensive patients. The impact of SPRINT on hypertension treatment has been large, but major questions remain about the feasibility of achieving the SPRINT intensive SBP target in routine practice, the generalizability of the SPRINT findings to hypertensive populations that were excluded from the trial, and the cost effectiveness of adopting the SPRINT intensive treatment goal. In this review, we discuss the generalizability of SPRINT data to the general population of adults with hypertension and with various comorbidities, the cost effectiveness of intensive SBP-lowering therapy, and the implications of SPRINT for future hypertension guideline development and clinical practice.
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Common Cardiovascular Complications of Cancer Therapy: Epidemiology, Risk Prediction, and Prevention
Vivek Narayan, and Bonnie KyVol. 69 (2018), pp. 97–111More LessThere is growing awareness of the overlap between oncologic and cardiovascular (CV) diseases, including a wide range of CV effects of anticancer therapies. As novel anticancer therapeutics become available and cancer survival outcomes improve, the CV implications of cancer therapy become increasingly important. In addition to outlining the CV effects of commonly used cancer therapies and their consequences for long-term survivorship, this review highlights the recent efforts to improve the risk prediction and prevention of CV toxicity through the evaluation of sensitive measures for early toxicity detection and the implementation of cardioprotective strategies.
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New Therapeutic Approaches for Familial Hypercholesterolemia
Vol. 69 (2018), pp. 113–131More LessFamilial hypercholesterolemia (FH) is a common genetic condition characterized by elevated plasma levels of low-density lipoprotein cholesterol (LDL-C), premature atherosclerotic cardiovascular disease, and considerable unmet medical need with conventional LDL-C-lowering therapies. Between 2012 and 2015, the US Food and Drug Administration approved four novel LDL-C-lowering agents for use in patients with FH based on the pronounced LDL-C-lowering efficacy of these medicines. We review the four novel approved agents, as well as promising LDL-C-lowering agents in clinical development, with a focus on their mechanism of action, efficacy in FH cohorts, and safety.
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PCSK9 Inhibitors: Mechanisms of Action, Metabolic Effects, and Clinical Outcomes
Vol. 69 (2018), pp. 133–145More LessAtherosclerotic cardiovascular disease (ASCVD) is associated with significant morbidity and mortality worldwide. Increased serum levels of low-density lipoprotein cholesterol (LDL-C) are an independent risk factor for ASCVD, and clinical trial data have shown that lowering LDL-C generally reduces cardiovascular risk. Until recently, 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) have been the main therapy for lowering LDL-C. However, some statin-treated patients have persistently elevated residual cardiovascular risk due to inadequate lowering of LDL-C levels or non-LDL-related dyslipidemia. In addition, adverse effects of statins may limit their tolerability and therefore the ability to attain effective doses in some patients. A new class of drugs that inhibit proprotein convertase subtilisin-kexin type 9 (PCSK9) has been developed to treat hyperlipidemia. This review discusses the history and mechanism of action of PCSK9 inhibitors, their metabolic effects, and clinical outcomes associated with these medications, highlighting recent large cardiovascular outcome trials investigating these therapies.
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Risk Stratification for Sudden Cardiac Death After Myocardial Infarction
Vol. 69 (2018), pp. 147–164More LessSudden cardiac death (SCD) accounts for ∼50% of mortality after myocardial infarction (MI). Most SCDs result from ventricular tachyarrhythmias, and the tachycardias that precipitate cardiac arrest result from multiple mechanisms. As a result, it is highly unlikely that any single test will identify all patients at risk for SCD. Current guidelines for use of implantable cardioverter-defibrillators (ICDs) to prevent SCD are based primarily on measurement of left ventricular ejection fraction (LVEF). Although reduced LVEF is associated with increased total cardiac mortality after MI, the focus of current guidelines on LVEF omits ∼50% of patients who die suddenly. In addition, there is no evidence of a mechanistic link between reduced LVEF and arrhythmias. Thus, LVEF is neither sensitive nor specific as a tool for post-MI risk stratification. Newer tests to screen for predisposition to ventricular arrhythmias and SCD examine abnormalities of ventricular repolarization, autonomic nervous system function, and electrical heterogeneity. These tests, as well as older methods such as programmed stimulation, the signal-averaged electrocardiogram, and spontaneous ventricular ectopy, do not perform well in patients with LVEF ≤30%. Recent observational studies suggest, however, that these tests may have greater utility in patients with LVEF >30%. Because SCD results from multiple mechanisms, it is likely that combinations of risk factors will prove more precise for risk stratification. Prospective trials that evaluate the performance of risk stratification schema to determine ICD use are necessary for cost-effective reduction of the incidence of SCD after MI.
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Understanding Peripartum Cardiomyopathy
Vol. 69 (2018), pp. 165–176More LessPeripartum cardiomyopathy (PPCM) is the unexplained loss of maternal cardiac systolic function in the period surrounding parturition. PPCM affects women worldwide and is a leading cause of maternal mortality. The cause of PPCM has remained elusive until recently. We review here the epidemiology of PPCM, recent findings that strongly indicate hormonal and genetic contributions to the development of PPCM, and implications for the management of women with PPCM.
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Updated Recommendations for Athletes with Heart Disease
Vol. 69 (2018), pp. 177–189More LessProfessional society recommendations to decrease sudden cardiac death in athletes, including eligibility requirements with disqualification for athletes with diagnosed disease as well as preparticipation screening and emergency preparedness, were updated in 2015. The update includes new sections on aortic disease, channelopathies, and sickle cell trait, as well as a change in format from the previous binary yes/no format to the more nuanced and contemporary “class and level of evidence” format. Eighty-four of the 246 recommendations now carry Class II designation—“reasonable,” or “may be considered.” New language in the document emphasizes counseling as part of the decision process. New data on athletes with implantable cardioverter-defibrillators, and on those with long QT syndrome, have led to a change from blanket restriction of competitive sports participation to a Class IIB “may be considered” recommendation.
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Antibody–Drug Conjugates for Cancer Treatment
Vol. 69 (2018), pp. 191–207More LessThe concept of exploiting the specific binding properties of monoclonal antibodies as a mechanism for selective delivery of cytotoxic agents to tumor cells is an attractive solution to the challenge of increasing the therapeutic index of cell-killing agents for treating cancer. All three parts of an antibody–drug conjugate (ADC)—the antibody, the cytotoxic payload, and the linker chemistry that joins them together—as well as the biologic properties of the cell-surface target antigen are important in designing an effective anticancer agent. The approval of brentuximab vedotin in 2011 for treating relapsed Hodgkin's lymphoma and systemic anaplastic large cell lymphoma, and the approval of ado-trastuzumab emtansine in 2013 for treating HER2-positive metastatic breast cancer, have sparked vigorous research in the field, with >65 ADCs currently in clinical evaluation. This review highlights the ADCs that are approved for marketing, in pivotal clinical trials, or in at least phase II clinical development for treating both hematologic malignancies and solid tumors.
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Modern Systemic Therapy for Metastatic Renal Cell Carcinoma of the Clear Cell Type
Vol. 69 (2018), pp. 209–221More LessIn the last 30 years, there have been many advances in the treatment of metastatic renal cell carcinoma of the clear cell type. Renal cell carcinoma has long been understood to have a component of immune mediation and has been responsive to immune-based therapies; in addition to early cytokine therapy, newer checkpoint inhibition therapies have also demonstrated activity. Molecular characterization of the genome of clear cell renal cell carcinoma enabled identification of the roles of angiogenesis and hypoxic stress. This led to development of small-molecule tyrosine kinase inhibitors and inhibitors of mammalian target of rapamycin that have provided additional benefit to patients. Ongoing strategies of combinations of immune and antiangiogenic therapies may lead to further advancements.
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Circulating Tumor DNA: Measurement and Clinical Utility
Vol. 69 (2018), pp. 223–234More LessCirculating tumor DNA (ctDNA) is a component of the “naked” DNA found in blood. It can be isolated from plasma and represents combined genetic material from the primary tumor and metastases. Quantitative and qualitative information about a cancer, including mutations, can be derived using digital polymerase chain reaction and other technologies. This “liquid biopsy” is quicker and more easily repeated than tissue biopsy, yields real-time information about the cancer, and may suggest therapeutic options. All stages of cancer therapy have the ability to benefit from ctDNA, starting with screening for cancer before it is clinically apparent. During treatment of metastatic disease, it is useful to predict response and monitor disease progression. Currently, ctDNA is used in the clinic to select patients who may benefit from epidermal growth factor receptor–targeted therapy in non–small cell lung cancer. In the future, ctDNA technology promises useful applications in every part of clinical oncology care.
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Computed Tomography Scanning for Early Detection of Lung Cancer
Vol. 69 (2018), pp. 235–245More LessParallel and often unrelated developments in health care and technology have all been necessary to bring about early detection of lung cancer and the opportunity to decrease mortality from lung cancer through early detection of the disease by computed tomography. Lung cancer screening programs provide education for patients and clinicians, support smoking cessation as primary prevention for lung cancer, and facilitate health care for tobacco-associated diseases, including cardiovascular and chronic lung diseases. Guidelines for lung cancer screening will need to continue to evolve as additional risk factors and screening tests are developed. Data collection from lung cancer screening programs is vital to the further development of fiscally responsible guidelines to increase detection of lung cancer, which may include small groups with elevated risk for reasons other than tobacco exposure.
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Evidence for Genetic Risk Contributing to Long-Term Adverse Treatment Effects in Childhood Cancer Survivors
Vol. 69 (2018), pp. 247–262More LessSurvivors of childhood cancer are at increased risk for therapy-related morbidities and mortality. Although the demographic and clinical factors predicting the risk for long-term effects of cancer therapy are well known, the impact of genetic risk for specific late effects is less clearly defined. Here, we review the extant literature and recent research describing genetic modifiers to risk for the more common late effects of childhood cancer therapy. Results of this research support the need for clinical trials that attempt to further refine risk prediction by incorporating genetic testing into existing algorithms that are primarily based on clinical and demographic factors. Confirmation of genetic predisposition, as defined by reproducibility and prospective validation, would permit therapeutic modification and discussion of individualized survivor care plans even at initial cancer diagnosis.
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Lymphedema: Pathogenesis and Novel Therapies
Vol. 69 (2018), pp. 263–276More LessLymphedema affects up to 1 in 6 patients who undergo treatment for a solid tumor in the United States. Its prevalence has increased as more effective oncologic therapies have improved patient survival, but there remains no definitive cure. Recent research has elucidated new details in the pathogenesis of the disease and has demonstrated that it is fundamentally an immunologic process that ultimately results in inflammation, fibroadipose deposition, impaired lymphangiogenesis, and dysfunctional lymphatic pumping. These findings have allowed for the development of novel medical and surgical therapies that may potentially alter the standard of care for a disease that has largely been treated by compression. This review seeks to provide an overview of the emerging therapies and how they can be utilized for effective management of lymphedema.
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Novel Radiotherapy Techniques for Breast Cancer
Vol. 69 (2018), pp. 277–288More LessDuring the early decades of radiation therapy for breast cancer, local control of disease was documented consistently but, enigmatically, an anticipated impact on breast cancer survival was not observed, leading to confusion in our understanding of the natural history of breast cancer and radiation effects. Now, almost 90 years after its first use in breast cancer, technology developments in diagnostic imaging and radiation therapy have elucidated parts of this enigma. The data now available demonstrate a significant impact of radiation therapy on survival as well as disease control and treatment-related mortality, opening a doorway to understanding the powerful impact of radiation therapy on both breast cancer and critical organs. Efforts are focused on leveraging novel techniques to maximize the benefits of radiation for breast cancer patients.
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Recombinant Poliovirus for Cancer Immunotherapy
Vol. 69 (2018), pp. 289–299More LessMechanisms to elicit antiviral immunity, a natural host response to viral pathogen challenge, are of eminent relevance to cancer immunotherapy. “Oncolytic” viruses, naturally existing or genetically engineered viral agents with cell type-specific propagation in malignant cells, were ostensibly conceived for their tumor cytotoxic properties. Yet, their true therapeutic value may rest in their ability to provoke antiviral signals that engage antitumor immune responses within the immunosuppressive tumor microenvironment. Coopting oncolytic viral agents to instigate antitumor immunity is not an easy feat. In the course of coevolution with their hosts, viruses have acquired sophisticated strategies to block inflammatory signals, intercept innate antiviral interferon responses, and prevent antiviral effector responses, e.g., by interfering with antigen presentation and T cell costimulation. The resulting struggle of host innate inflammatory and antiviral responses versus viral immune evasion and suppression determines the potential for antitumor immunity to occur. Moreover, paradigms of early host:virus interaction established in normal immunocompetent organisms may not hold in the profoundly immunosuppressive tumor microenvironment. In this review, we explain the mechanisms of recombinant nonpathogenic poliovirus, PVSRIPO, which is currently in phase I clinical trials against recurrent glioblastoma. We focus on an unusual host:virus relationship defined by the simple and cytotoxic replication strategy of poliovirus, which generates inflammatory perturbations conducive to tumor antigen-specific immune priming.
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CD8 T Cell Exhaustion in Chronic Infection and Cancer: Opportunities for Interventions
Vol. 69 (2018), pp. 301–318More LessAntigen-specific CD8 T cells are central to the control of chronic infections and cancer, but persistent antigen stimulation results in T cell exhaustion. Exhausted CD8 T cells have decreased effector function and proliferative capacity, partly caused by overexpression of inhibitory receptors such as programmed cell death (PD)-1. Blockade of the PD-1 pathway has opened a new therapeutic avenue for reinvigorating T cell responses, with positive outcomes especially for patients with cancer. Other strategies to restore function in exhausted CD8 T cells are currently under evaluation—many in combination with PD-1-targeted therapy. Exhausted CD8 T cells comprise heterogeneous cell populations with unique differentiation and functional states. A subset of stem cell–like PD-1+ CD8 T cells responsible for the proliferative burst after PD-1 therapy has been recently described. A greater understanding of T cell exhaustion is imperative to establish rational immunotherapeutic interventions.
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Basket Studies: Redefining Clinical Trials in the Era of Genome-Driven Oncology
Vol. 69 (2018), pp. 319–331More LessUnderstanding a tumor's detailed molecular profile has become increasingly necessary to deliver the standard of care for patients with advanced cancer. Innovations in both tumor genomic sequencing technology and the development of drugs that target molecular alterations have fueled recent gains in genome-driven oncology care. “Basket studies,” or histology-agnostic clinical trials in genomically selected patients, represent one important research tool to continue making progress in this field. We review key aspects of genome-driven oncology care, including the purpose and utility of basket studies, biostatistical considerations in trial design, genomic knowledgebase development, and patient matching and enrollment models, which are critical for translating our genomic knowledge into clinically meaningful outcomes.
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Molecular and Genomic Determinants of Response to Immune Checkpoint Inhibition in Cancer
Vol. 69 (2018), pp. 333–347More LessMolecularly targeted therapy and immunotherapy have dramatically changed the landscape of available treatment options for patients with advanced cancer. Improved understanding of the molecular and genomic features of cancers over the last decade has led to the development of successful targeted therapies and the field of precision cancer medicine. As a result of these advances, patients whose tumors harbor select molecular alterations are eligible for treatment with targeted therapies active against the unique molecular aberration. Concurrently, advances in tumor immunology have led to the development of immunomodulatory antibodies targeting T cell coinhibitory receptors CTLA-4 and PD-1 (programmed death–1) that have shown activity in several cancer histologies, reinvigorating antitumor immune responses in a subset of patients. These immunomodulatory antibodies offer the promise of durable disease control. However, discrete genomic determinants of response to cancer immunotherapy, unlike molecularly targeted therapies, have remained elusive, and robust biomarkers are lacking. Recent advances in tumor profiling have begun to identify novel genomic features that may influence response and resistance to cancer immunotherapy, including tumor mutational burden (e.g., microsatellite instability), copy-number alterations, and specific somatic alterations that influence immune recognition and response. Further investigation into the molecular and genomic features of response and resistance to cancer immunotherapy will be needed. We review the recent advances in understanding the molecular and genomic determinants of response to cancer immunotherapy, with an emphasis on immune checkpoint inhibitors.
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Targeting RAGE Signaling in Inflammatory Disease
Vol. 69 (2018), pp. 349–364More LessThe receptor for advanced glycation end-products (RAGE) is a multiligand pattern recognition receptor implicated in diverse chronic inflammatory states. RAGE binds and mediates the cellular response to a range of damage-associated molecular pattern molecules (DAMPs) including AGEs, HMGB1, S100s, and DNA. RAGE can also act as an innate immune sensor of microbial pathogen-associated molecular pattern molecules (PAMPs) including bacterial endotoxin, respiratory viruses, and microbial DNA. RAGE is expressed at low levels under normal physiology, but it is highly upregulated under chronic inflammation because of the accumulation of various RAGE ligands. Blocking RAGE signaling in cell and animal models has revealed that targeting RAGE impairs inflammation and progression of diabetic vascular complications, cardiovascular disease (CVD), and cancer progression and metastasis. The clinical relevance of RAGE in inflammatory disease is being demonstrated in emerging clinical trials of novel small-molecule RAGE inhibitors.
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New Concepts in the Treatment of Malignant Pleural Mesothelioma
Vol. 69 (2018), pp. 365–377More LessMalignant pleural mesothelioma (MPM) is a highly aggressive and generally incurable cancer. Current anti-MPM chemotherapy-based treatments are only marginally effective, and long-term survival remains an unmet goal. Nonetheless, in selected cases, personalized surgery-based multimodality treatments (MMT) have been shown to significantly extend survival. The design of MMT and selection of patients are challenging, and optimal results require accurate presurgical diagnosis, staging, and risk stratification. Further, meticulous surgical techniques and advanced radiation protocols must be applied. We review key principles and evolving concepts in the care of MPM patients with a focus on the expanding role of MMT in MPM.
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New Molecular Diagnostic Approaches to Bacterial Infections and Antibacterial Resistance
Vol. 69 (2018), pp. 379–394More LessRecent advances in the field of infectious disease diagnostics have given rise to a number of host- and pathogen-centered diagnostic approaches. Most diagnostic approaches in contemporary infectious disease focus on pathogen detection and characterization. Host-focused diagnostics have recently emerged and are based on detecting the activation of biological pathways that are highly specific to the type of infecting pathogen (e.g., viral, bacterial, protozoan, fungal). Although this progress is encouraging, it is unlikely that any single diagnostic platform will fully address the clinician's need for actionable data with short turnaround times in all settings.
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Zika, Chikungunya, and Other Emerging Vector-Borne Viral Diseases
Vol. 69 (2018), pp. 395–408More LessArthropod-borne viruses (arboviruses) have a long history of emerging to infect humans, but during recent decades, they have been spreading more widely and affecting larger populations. This is due to several factors, including increased air travel and uncontrolled mosquito vector populations. Emergence can involve simple spillover from enzootic (wildlife) cycles, as in the case of West Nile virus accompanying geographic expansion into the Americas; secondary amplification in domesticated animals, as seen with Japanese encephalitis, Venezuelan equine encephalitis, and Rift Valley fever viruses; and urbanization, in which humans become the amplification hosts and peridomestic mosquitoes, mainly Aedes aegypti, mediate human-to-human transmission. Dengue, yellow fever, chikungunya, and Zika viruses have undergone such urban emergence. We focus mainly on the latter two, which are recent arrivals in the Western Hemisphere. We also discuss a few other viruses with the potential to emerge through all of these mechanisms.
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New-Generation High-Potency and Designer Antibodies: Role in HIV-1 Treatment
Vol. 69 (2018), pp. 409–419More LessBroadly neutralizing antibodies (bNAbs) have been evaluated as promising agents in the fight against infectious diseases. HIV-1-specific bNAbs, in particular, have been tested in both preventive and therapeutic modalities. Multiple bNAbs have been isolated, characterized, and assessed in vitro and in vivo, but no single antibody appears to possess the breadth and potency that may be needed if it is to be used in the treatment of HIV-1 infection. With the technological advances of the past decades, novel and more effective bNAbs have been identified or engineered for higher neutralizing potency, greater breadth, and increased serum half-life. In this review, we discuss the development of a new generation of anti-HIV-1 bNAbs and their potential to be used clinically for treatment and prevention of HIV-1 infection.
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Novel Latency Reversal Agents for HIV-1 Cure
Vol. 69 (2018), pp. 421–436More LessAntiretroviral therapy (ART) has rendered HIV-1 infection a treatable illness; however, ART is not curative owing to the persistence of replication-competent, latent proviruses in long-lived resting T cells. Strategies that target these latently infected cells and allow immune recognition and clearance of this reservoir will be necessary to eradicate HIV-1 in infected individuals. This review describes current pharmacologic approaches to reactivate the latent reservoir so that infected cells can be recognized and targeted, with the ultimate goal of achieving an HIV-1 cure.
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Innate Immunity and Neurodegeneration
Vol. 69 (2018), pp. 437–449More LessThe innate immune system plays diverse roles in health and disease. It represents the first line of defense against infection and is involved in tissue repair, wound healing, and clearance of apoptotic cells and cellular debris. Excessive or nonresolving innate immune activation can lead to systemic or local inflammatory complications and cause or contribute to the development of inflammatory diseases. In the brain, microglia represent the key innate immune cells, which are involved in brain development, brain maturation, and homeostasis. Impaired microglial function, either through aberrant activation or decreased functionality, can occur during aging and during neurodegeneration, and the resulting inflammation is thought to contribute to neurodegenerative diseases. This review highlights recent advances in our understanding of the influence of innate immunity on neurodegenerative disorders such as Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, and Huntington's disease.
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Use and Misuse of Opioids in Chronic Pain
Vol. 69 (2018), pp. 451–465More LessThe prescribing of opioid analgesics for pain management—particularly for management of chronic noncancer pain (CNCP)—has increased more than fourfold in the United States since the mid-1990s. Yet there is mounting evidence that opioids have only limited effectiveness in the management of CNCP, and the increased availability of prescribed opioids has contributed to upsurges in opioid-related addiction cases and overdose deaths. These concerns have led to critical revisiting and modification of prior pain management practices (e.g., guidelines from the Centers for Disease Control and Prevention), but the much-needed changes in clinical practice will be facilitated by a better understanding of the pharmacology and behavioral effects of opioids that underlie both their therapeutic effects (analgesia) and their adverse effects (addiction and overdose). With these goals in mind, this review first presents an overview of the contemporary problems associated with opioid management of CNCP and the related public health issues of opioid diversion, overdose, and addiction. It then discusses the pharmacology underlying the therapeutic and main adverse effects of opioids and its implications for clinical management of CNCP within the framework of recent clinical guidelines for prescribing opioids in the management of CNCP.
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Measuring Patient-Reported Outcomes: Key Metrics in Reconstructive Surgery
Vol. 69 (2018), pp. 467–479More LessSatisfaction and improved quality of life are among the most important outcomes for patients undergoing plastic and reconstructive surgery for a variety of diseases and conditions. Patient-reported outcome measures (PROMs) are essential tools for evaluating the benefits of newly developed surgical techniques. Modern PROMs are being developed with new psychometric approaches, such as Rasch Measurement Theory, and their measurement properties (validity, reliability, responsiveness) are rigorously tested. These advances have resulted in the availability of PROMs that provide clinically meaningful data and effectively measure functional as well as psychosocial outcomes. This article guides the reader through the steps of creating a PROM and highlights the potential research and clinical uses of such instruments. Limitations of PROMs and anticipated future directions in this field are discussed.
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What Metrics Accurately Reflect Surgical Quality?
Vol. 69 (2018), pp. 481–491More LessSurgeons are increasingly under pressure to measure and improve their quality. While there is broad consensus that we ought to track surgical quality, there is far less agreement about which metrics matter most. This article reviews the important statistical concepts of case mix and chance as they apply to understanding the observed wide variation in surgical quality. We then discuss the benefits and drawbacks of current measurement strategies through the framework of structure, process, and outcomes approaches. Finally, we describe emerging new metrics, such as video evaluation and network optimization, that are likely to take on an increasingly important role in the future of measuring surgical quality.
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Previous Volumes
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Volume 75 (2024)
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Volume 74 (2023)
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Volume 73 (2022)
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Volume 72 (2021)
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Volume 71 (2020)
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Volume 70 (2019)
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Volume 69 (2018)
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Volume 68 (2017)
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Volume 67 (2016)
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Volume 66 (2015)
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Volume 65 (2014)
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Volume 64 (2013)
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Volume 63 (2012)
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