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  • Cardiac Pacing and Defibrillation Devices: Cost and Effectiveness
    Annu. Rev. Med. (IF 13.609) Pub Date : 2017-01-18
    Peter W. Groeneveld, Sanjay Dixit

    Implantable cardiac pacing and defibrillation devices are effective and commonly used therapies for patients with cardiac rhythm disorders. Because device implantation is not easily reversible, as well as the high healthcare costs inherent in device use, a clear understanding of the clinical benefits relative to costs is essential for both appropriate clinical use and rational policy making. Cardiac implantable electronic devices (CIEDs) have been among the best-investigated therapies in medicine; these devices have been the topic of numerous clinical and economic evaluations during the past 30 years. However, many important questions remain unclarified. We review the evidence supporting the clinical benefits of CIEDs, including effectiveness in extending survival as well as improving quality of life. We also summarize the economic studies that have investigated costs associated with these devices and their overall cost effectiveness, and we highlight important potential areas for future research.

    更新日期:2017-06-21
  • Transcatheter Aortic Valve Replacement: State of the Art and Future Directions
    Annu. Rev. Med. (IF 13.609) Pub Date : 2017-01-18
    Mackram F. Eleid, David R. Holmes Jr.

    Transcatheter aortic valve replacement (TAVR) is a transformational and rapidly evolving treatment for patients with aortic stenosis who require valve replacement. Novel technological advancements have made this percutaneous minimally invasive therapy a first-line treatment for many patients at extreme risk for conventional cardiac surgery. New devices and improvements in existing devices have reduced procedural complications, and scientific trials are investigating the role of TAVR in lower-risk aortic stenosis populations, in patients with aortic regurgitation, and in patients with bicuspid aortic valve disease. Finally, there is intense interest in identifying patients in whom the risk-benefit ratio of TAVR is not favorable and should not be performed.

    更新日期:2017-06-21
  • Tissue Engineering: Toward a New Era of Medicine
    Annu. Rev. Med. (IF 13.609) Pub Date : 2017-01-18
    Ashkan Shafiee, Anthony Atala

    The goal of tissue engineering is to mitigate the critical shortage of donor organs via in vitro fabrication of functional biological structures. Tissue engineering is one of the most prominent examples of interdisciplinary fields, where scientists with different backgrounds work together to boost the quality of life by addressing critical health issues. Many different fields, such as developmental and molecular biology, as well as technologies, such as micro- and nanotechnologies and additive manufacturing, have been integral for advancing the field of tissue engineering. Over the past 20 years, spectacular advancements have been achieved to harness nature's ability to cure diseased tissues and organs. Patients have received laboratory-grown tissues and organs made out of their own cells, thus eliminating the risk of rejection. However, challenges remain when addressing more complex solid organs such as the heart, liver, and kidney. Herein, we review recent accomplishments as well as challenges that must be addressed in the field of tissue engineering and provide a perspective regarding strategies in further development.

    更新日期:2017-06-21
  • Neprilysin Inhibitors: Emerging Therapy for Heart Failure
    Annu. Rev. Med. (IF 13.609) Pub Date : 2017-01-18
    Anjali Tiku Owens, Susan Brozena, Mariell Jessup

    Biologically active natriuretic peptides (NPs) are an integral part of cardiac homeostasis as they help to maintain sodium and fluid balance. When homeostasis is perturbed by neurohormonal activation in heart failure, levels of NPs rise in response. Neprilysin (NEP) is a naturally occuring enzyme that breaks down NPs. Scientists have recently discovered a novel pharmacologic agent that combines a NEP inhibitor and an angiotensin receptor blocker. In a large clinical trial, this new drug was found to reduce hospitalization and mortality in systolic heart failure. The challenges of implementing this therapy include patient selection, cost, and risk of side effects including angioedema and Alzheimer's disease.

    更新日期:2017-06-21
  • Therapeutics Targeting Drivers of Thoracic Aortic Aneurysms and Acute Aortic Dissections: Insights from Predisposing Genes and Mouse Models
    Annu. Rev. Med. (IF 13.609) Pub Date : 2017-01-18
    Dianna M. Milewicz, Siddharth K. Prakash, Francesco Ramirez

    Thoracic aortic diseases, including aneurysms and dissections of the thoracic aorta, are a major cause of morbidity and mortality. Risk factors for thoracic aortic disease include increased hemodynamic forces on the ascending aorta, typically due to poorly controlled hypertension, and heritable genetic variants. The altered genes predisposing to thoracic aortic disease either disrupt smooth muscle cell (SMC) contraction or adherence to an impaired extracellular matrix, or decrease canonical transforming growth factor beta (TGF-β) signaling. Paradoxically, TGF-β hyperactivity has been postulated to be the primary driver for the disease. More recently, it has been proposed that the response of aortic SMCs to the hemodynamic load on a structurally defective aorta is the primary driver of thoracic aortic disease, and that TGF-β overactivity in diseased aortas is a secondary, unproductive response to restore tissue function. The engineering of mouse models of inherited aortopathies has identified potential therapeutic agents to prevent thoracic aortic disease.

    更新日期:2017-06-21
  • Lymphangioleiomyomatosis: A Monogenic Model of Malignancy
    Annu. Rev. Med. (IF 13.609) Pub Date : 2017-01-18
    Vera P. Krymskaya, Francis X. McCormack

    Lymphangioleiomyomatosis (LAM) is a rare, low-grade, metastasizing neoplasm that arises from an unknown source, spreads via the lymphatics, and targets the lungs. All pulmonary structures become infiltrated with benign-appearing spindle and epithelioid cells (LAM cells) that express smooth-muscle and melanocyte-lineage markers, harbor mTOR-activating mutations in tuberous sclerosis complex (TSC) genes, and recruit abundant stromal cells. Elaboration of lymphangiogenic growth factors and matrix remodeling enzymes by LAM cells enables their access to lymphatic channels and likely drives the cystic lung remodeling that often culminates in respiratory failure. Dysregulated cellular signaling results in a shift from oxidative phosphorylation to glycolysis as the preferred mode of energy generation, to allow for the accumulation of biomass required for cell growth and tolerance of nutrient-poor, anaerobic environments. Symptomatic LAM occurs almost exclusively in females after menarche, highlighting the central but as yet poorly understood role for sex-restricted anatomical structures and/or hormones in disease pathogenesis. LAM is an elegant model of malignancy because biallelic mutations at a single genetic locus confer all features that define cancer upon the LAM cell—metabolic reprogramming and proliferative signals that drive uncontrolled growth and inappropriate migration and invasion, the capacity to exploit the lymphatic circulation as a vehicle for metastasis and access to the lungs, and destruction of remote tissues. The direct benefit of the study of this rare disease has been the rapid identification of an effective FDA-approved therapy, and the collateral benefits have included elucidation of the pivotal roles of mTOR signaling in the regulation of cellular metabolism and the pathogenesis of cancer.

    更新日期:2017-06-21
  • Nonalcoholic Steatohepatitis
    Annu. Rev. Med. (IF 13.609) Pub Date : 2017-01-18
    Ayako Suzuki, Anna Mae Diehl

    Nonalcoholic steatohepatitis (NASH) has become a major cause of cirrhosis and liver-related deaths worldwide. NASH is strongly associated with obesity and the metabolic syndrome, conditions that cause lipid accumulation in hepatocytes (hepatic steatosis). It is not well understood why some, but not other, individuals with hepatic steatosis develop NASH. The factors that determine whether or not NASH progresses to cirrhosis are also unclear. This review summarizes key components of NASH pathogenesis and discusses how inherent and acquired variations in regulation of these processes impact the risk for NASH and NASH cirrhosis.

    更新日期:2017-06-21
  • Obstructive Sleep Apnea: Update and Future
    Annu. Rev. Med. (IF 13.609) Pub Date : 2017-01-18
    Diane C. Lim, Allan I. Pack

    Obstructive sleep apnea (OSA) is a worldwide disease whose prevalence is increasing as obesity rates increase. The link between obesity and OSA is likely to be the deposition of fat in the tongue, compromising upper airway size. The role of obesity varies in different ethnic groups, with Chinese being particularly sensitive to increases in weight. OSA lends itself to a personalized approach to diagnosis and therapy. For example, different clinical OSA subtypes likely benefit from therapy in different ways. Hypoglossal nerve stimulation is a useful second-line therapy in patients who cannot tolerate continous positive airway pressure (CPAP) machines or intraoral devices. Technological advances allow patients to participate in their own care, and doing so improves CPAP compliance. We are entering a future where we can focus efforts to predict and prevent OSA on an individual level.

    更新日期:2017-06-21
  • Next-Generation Sequencing and Result Interpretation in Clinical Oncology: Challenges of Personalized Cancer Therapy
    Annu. Rev. Med. (IF 13.609) Pub Date : 2017-01-18
    Yekaterina B. Khotskaya, Gordon B. Mills, Kenna R. Mills Shaw

    The tools of next-generation sequencing (NGS) technology, such as targeted sequencing of candidate cancer genes and whole-exome and -genome sequencing, coupled with encouraging clinical results based on the use of targeted therapeutics and biomarker-guided clinical trials, are fueling further technological advancements of NGS technology. However, NGS data interpretation is associated with challenges that must be overcome to promote the techniques' effective integration into clinical oncology practice. Specifically, sequencing of a patient's tumor often yields 30–65 somatic variants, but most of these variants are “passenger” mutations that are phenotypically neutral and thus not targetable. Therefore, NGS data must be interpreted by multidisciplinary decision-support teams to determine mutation actionability and identify potential “drivers,” so that the treating physician can prioritize what clinical decisions can be pursued in order to provide cancer therapy that is personalized to the patient and his or her unique genome.

    更新日期:2017-06-21
  • Precision Medicine in Myelodysplastic Syndromes and Leukemias: Lessons from Sequential Mutations
    Annu. Rev. Med. (IF 13.609) Pub Date : 2017-01-18
    Aziz Nazha, Mikkael A. Sekeres

    Precision medicine can be simply defined as the identification of personalized treatment that matches patient-specific clinical and genomic characteristics. Since the completion of the Human Genome Project in 2003, significant advances have been made in our understanding of the genetic makeup of diseases, especially cancers. The identification of somatic mutations that can drive cancer has led to the development of therapies that specifically target the abnormal proteins derived from these mutations. This has led to a paradigm shift in our treatment methodology. Although some success has been achieved in targeting some genetic abnormalities, several challenges and limitations exist when applying precision-medicine concepts in leukemia and myelodysplastic syndromes. We review the current understanding of genomics in myelodysplastic syndromes (MDS) and leukemias and the limitations of precision-medicine concepts in MDS.

    更新日期:2017-06-21
  • CAR T Cell Therapy for Solid Tumors
    Annu. Rev. Med. (IF 13.609) Pub Date : 2017-01-18
    Kheng Newick, Shaun O'Brien, Edmund Moon, Steven M. Albelda

    The field of cancer immunotherapy has been re-energized by the application of chimeric antigen receptor (CAR) T cell therapy in cancers. These CAR T cells are engineered to express synthetic receptors that redirect polyclonal T cells to surface antigens for subsequent tumor elimination. Many CARs are designed with elements that augment T cell persistence and activity. To date, CAR T cells have demonstrated tremendous success in eradicating hematologic malignancies (e.g., CD19 CARs in leukemias). However, this success has yet to be extrapolated to solid tumors, and the reasons for this are being actively investigated. We characterize some of the challenges that CAR T cells have to surmount in the solid tumor microenvironment and new approaches that are being considered to overcome these hurdles.

    更新日期:2017-06-21
  • The End of Nihilism: Systemic Therapy of Advanced Non–Small Cell Lung Cancer
    Annu. Rev. Med. (IF 13.609) Pub Date : 2017-01-18
    Vinicius Ernani, Conor E. Steuer, Mohammad Jahanzeb

    Lung cancer is the leading cause of cancer death in the United States and many other parts of the world. Non–small cell lung cancer (NSCLC) comprises 85–90% of lung cancers. Historically, the expected survival of patients with advanced disease has been estimated in months. In recent years, however, lung cancer has come to be seen as a treatable disease with multiple therapeutic options. Enormous advances in the understanding of its pathways and mechanisms have enabled personalized therapy in NSCLC. The evolving approach to therapy focuses on genomic profiling of the tumors to find molecular targets and develop specific agents for individualized therapy. In addition, maintenance therapy has emerged as a valid approach, and the choice of chemotherapy now varies by histology. Most recently, immunotherapy with checkpoint inhibitors has shown promising results, with impressive durations of response and a tolerable toxicity profile. Together, these discoveries have improved overall survival substantially in patient populations that have access to these advancements. We review the clinical data surrounding these impressive improvements.

    更新日期:2017-06-21
  • Management of Rectal Cancer Without Radical Resection
    Annu. Rev. Med. (IF 13.609) Pub Date : 2017-01-18
    Geerard L. Beets, Nuno F. Figueiredo, Regina G.H. Beets-Tan

    The basis of the current treatment of rectal cancer is a radical total mesorectal excision of the rectum, and although this provides excellent oncological control, it is associated with morbidity and functional problems in cancer survivors. Organ-preservation alternatives are local excision alone for very early tumors, chemoradiation followed by either local excision of a small tumor remnant or, when there is a complete clinical response, a nonoperative watch-and-wait approach. The functional advantage of these alternatives is clear, but there is some concern about the oncological risk. Although the available studies suggest that with adequate selection and follow-up this risk is small, the evidence is still weak. Because of patients' high interest in preserving quality of life, clinicians should cautiously move ahead and offer the option of organ preservation to patients in a controlled setting while awaiting further evidence.

    更新日期:2017-06-21
  • Resection of Liver Metastases in Colorectal Cancer in the Era of Expanding Systemic Therapy
    Annu. Rev. Med. (IF 13.609) Pub Date : 2017-01-18
    Robert P. Jones, Graeme J. Poston

    About 25% of patients with colorectal cancer develop liver metastases after resection of the primary tumor, and surgical resection of the metastases offers the only opportunity for long-term survival. However, only 20% of patients present with resectable disease. Deciding which patients should be offered surgery, and which should receive additional treatment in the form of perioperative chemotherapy, is complex. For the majority of patients who present with technically irresectable liver-limited disease, systemic downsizing chemotherapy offers the only opportunity to reach surgery and potential cure. Molecular analysis of tumor tissue is improving patient stratification, allowing more appropriate treatment selection, but is not yet a regular part of clinical practice. Decision making is limited by a lack of clear prospective evidence, and so multidisciplinary team assessment is essential to optimize outcomes.

    更新日期:2017-06-21
  • Controversies in the Treatment of Ductal Carcinoma in Situ
    Annu. Rev. Med. (IF 13.609) Pub Date : 2017-01-18
    Andrea V. Barrio, Kimberly J. Van Zee

    Ductal carcinoma in situ (DCIS) accounts for 20% of all newly diagnosed breast cancers. Mastectomy was once the gold standard for the treatment of DCIS; however, breast-conserving surgery (BCS) has been adopted as the treatment of choice for patients with small, screen-detected lesions. Both adjuvant radiation and hormonal therapy following BCS have been demonstrated in randomized trials to reduce the risk of both invasive and DCIS recurrence, but neither affects survival. With the variety of surgical and adjuvant treatment options available, there has been great interest in tailoring the treatment to the individual, with the goal of optimizing the balance of risks and benefits according to the values and priorities of the woman herself. Prospective studies of women with “low-risk” DCIS treated with BCS alone have successfully identified women at lower than average risk but have not achieved the goal of identifying a subset of women with DCIS at minimal risk of recurrence after surgical excision alone. No studies have evaluated the safety of medical management alone.

    更新日期:2017-06-21
  • Esophageal Adenocarcinoma: Screening, Surveillance, and Management
    Annu. Rev. Med. (IF 13.609) Pub Date : 2017-01-18
    Nabil M. Mansour, Shawn S. Groth, Sharmila Anandasabapathy

    Esophageal adenocarcinoma (EAC) is a growing problem with a rapidly rising incidence. Risk factors include gastroesophageal reflux disease, central obesity, and smoking. The prognosis of EAC remains poor because it is usually diagnosed late, and many efforts have been made to improve prevention, early detection, and treatment. Acid suppression, nonsteroidal antiinflammatory drugs (NSAIDs), and statins may play a role in chemoprevention. Screening for Barrett's esophagus (BE), the only known precursor lesion of EAC, is indicated for individuals with increased risk. Endoscopic surveillance of patients with BE likely improves overall outcomes. Endoscopic ablation and resection is highly effective for treating dysplastic BE and early EAC, whereas esophagectomy is indicated for patients with locally advanced disease. This review covers epidemiology, staging, screening, and prevention of EAC as well as endoscopic and surgical management.

    更新日期:2017-06-21
  • Why Are There So Many Mastectomies in the United States?
    Annu. Rev. Med. (IF 13.609) Pub Date : 2017-01-18
    Anita Mamtani, Monica Morrow

    Breast-conserving therapy (BCT) and mastectomy result in equivalent long-term survival. Locoregional recurrence rates after BCT have decreased over time and are now similar to those after mastectomy. Contralateral breast cancer rates are declining as well owing to the widespread use of adjuvant systemic therapy. Despite these improved outcomes, increasing rates of bilateral mastectomy for unilateral cancer have been observed in the United States. Medical indications for mastectomy are well defined and present in a minority of patients, and women at increased risk for contralateral cancer are a small proportion of the breast cancer population. Evidence indicates that increasing use of mastectomy is a patient-driven trend that is most pronounced among younger, educated, and well-insured women, and reflects fear of recurrence and in some cases misunderstanding of future cancer risks. Although satisfaction levels are generally high among patients choosing contralateral prophylactic mastectomy, complications and procedure extent may be underestimated. Improved communication strategies are essential to facilitate this complex decision-making process.

    更新日期:2017-06-21
  • Biosimilars: The US Regulatory Framework*
    Annu. Rev. Med. (IF 13.609) Pub Date : 2017-01-18
    Leah A. Christl, Janet Woodcock, Steven Kozlowski

    With the passage of the Biologics Price Competition and Innovation Act of 2009, the US Food and Drug Administration established an abbreviated pathway for developing and licensing biosimilar and interchangeable biological products. The regulatory framework and the technical requirements of the US biosimilars program involve a stepwise approach that relies heavily on analytical methods to demonstrate through a “totality of the evidence” that a proposed product is biosimilar to its reference product. By integrating analytical, pharmacological, and clinical data, each of which has limitations, a high level of confidence can be reached regarding clinical performance. Although questions and concerns about the biosimilars pathway remain and may slow uptake, a robust scientific program has been put in place. With three biosimilars already licensed and numerous development programs under way, clinicians can expect to see many new biosimilars come onto the US market in the coming decade. [Note added in proof: Since the writing of this article, a fourth biosimilar has been approved.]

    更新日期:2017-06-21
  • Highly Effective New Treatments for Psoriasis Target the IL-23/Type 17 T Cell Autoimmune Axis
    Annu. Rev. Med. (IF 13.609) Pub Date : 2017-01-18
    Jaehwan Kim, James G. Krueger

    Psoriasis vulgaris, affecting the skin, is one of the most common organ-specific autoimmune diseases in humans. Until recently, psoriasis was treated by agents or approaches discovered largely through serendipity. Many of the available drugs were inherently quite toxic when used as continuous treatment for many years in this chronic disease. However, an increasing understanding of disease-specific immune pathways has spurred development of pathway-targeted therapeutics during the past decade. Psoriasis is now the most effectively treated human autoimmune disease, with high-level clinical improvements possible in ∼90% of patients using a new generation of drugs that selectively target the IL-23/Type 17 T cell axis. Thus, psoriasis is a model for the success of a translational-medicine approach based on cellular and molecular dissection of disease pathogenesis in humans.

    更新日期:2017-06-21
  • Management of Systemic Lupus Erythematosus During Pregnancy
    Annu. Rev. Med. (IF 13.609) Pub Date : 2017-01-18
    Lisa R. Sammaritano

    Reproductive issues including contraception, fertility, and pregnancy are important components of the comprehensive care of women with systemic lupus erythematosus (SLE). SLE pregnancies are complicated due to risk for maternal disease exacerbation and potential for fetal and neonatal complications. Pre-pregnancy assessment is important to identify patients with severe disease-related damage who should avoid pregnancy, counsel patients to conceive when disease has been stable and inactive on appropriate medications, and assess relevant risk factors including renal disease, antiphospholipid antibody, and anti-Ro/SS-A and anti-La/SS-B antibodies. With careful planning, monitoring, and care, most women with SLE can anticipate a successful pregnancy.

    更新日期:2017-06-21
  • Catastrophic Antiphospholipid Syndrome: Candidate Therapies for a Potentially Lethal Disease
    Annu. Rev. Med. (IF 13.609) Pub Date : 2017-01-18
    Ozan Unlu, Doruk Erkan

    Catastrophic antiphospholipid syndrome (CAPS) is a potentially lethal disease that presents with rapidly progressive multiple organ thromboses. Anticoagulation, corticosteroids, intravenous immunoglobulin, and plasma exchange are the most commonly used treatments for CAPS patients. However, the high mortality despite these medications necessitates new treatment strategies. Following a brief review of current diagnostic and management strategies, we discuss the candidate therapies, i.e., hydroxychloroquine, rituximab, eculizumab, sirolimus, and defibrotide, that can be considered in CAPS patients refractory to traditional treatment.

    更新日期:2017-06-21
  • The Type I Interferonopathies
    Annu. Rev. Med. (IF 13.609) Pub Date : 2017-01-18
    Min Ae Lee-Kirsch

    Type I interferons (IFNs) play a central role in the immune defense against viral infections. Type I IFN activation is induced by pattern-recognition receptors of the innate immune system that sense pathogen-derived nucleic acids. Cellular responses to type I IFN signaling are orchestrated by a complex network of regulatory pathways that involve both the innate and adaptive immune system. The genetic and molecular dissection of rare Mendelian disorders associated with constitutive overproduction of type I IFN has provided unique insight into cell-intrinsic disease mechanisms that initiate and sustain autoinflammation and autoimmunity and that are caused by disturbances in the intracellular nucleic acid metabolism or in cytosolic nucleic acid–sensing pathways. Collectively, these findings have greatly advanced our understanding of mechanisms that protect the organism against inappropriate immune activation triggered by self nucleic acids while maintaining a prompt and efficient immune response to foreign nucleic acids derived from invading pathogens.

    更新日期:2017-06-21
  • Antimalarial Drugs as Immune Modulators: New Mechanisms for Old Drugs
    Annu. Rev. Med. (IF 13.609) Pub Date : 2017-01-18
    Jie An, Mark Minie, Tomikazu Sasaki, Joshua J. Woodward, Keith B. Elkon

    The best known of the naturally occurring antimalarial compounds are quinine, extracted from cinchona bark, and artemisinin (qinghao), extracted from Artemisia annua in China. These and other derivatives are now chemically synthesized and remain the mainstay of therapy to treat malaria. The beneficial effects of several of the antimalarial drugs (AMDs) on clinical features of autoimmune disorders were discovered by chance during World War II. In this review, we discuss the chemistry of AMDs and their mechanisms of action, emphasizing how they may impact multiple pathways of innate immunity. These pathways include Toll-like receptors and the recently described cGAS-STING pathway. Finally, we discuss the current and future impact of AMDs on systemic lupus erythematosus, rheumatoid arthritis, and devastating monogenic disorders (interferonopathies) characterized by expression of type I interferon in the brain.

    更新日期:2017-06-21
  • Mechanisms and New Strategies for Primary Sjögren's Syndrome
    Annu. Rev. Med. (IF 13.609) Pub Date : 2017-01-18
    Clio P. Mavragani

    Primary Sjögren's syndrome (SS) is a common chronic autoimmune disease characterized by lymphocytic infiltration of exocrine glands, mainly salivary and lacrimal, resulting in oral and ocular dryness, although virtually any organ system can be affected. SS-related systemic manifestations are classified as either related to the presence of periepithelial infiltrates in exocrine and parenchymal organs or resulting from immunocomplex deposition due to B cell hyperactivity with increased risk for B cell lymphoma development. Activation of both innate and adaptive immune pathways contributes to disease pathogenesis, with prominent interferon (IFN) signatures identified in both peripheral blood and affected salivary gland tissues. Recently, LINE-1 genomic repeat elements have been proposed as potential triggers of type I IFN pathway activation in SS through activation of Toll-like receptor–dependent and –independent pathways. In view of the increasingly appreciated variability of SS, elucidation of distinct operating pathways in relation to diverse clinical phenotypes and selection of the optimal therapeutic intervention remain major challenges. Inhibition of cathepsin S molecules, blockade of costimulation through administration of abatacept and inhibitors of B7-related molecules and CD40, blockade of B cell function and B cell survival factors, and disruption of the formation of ectopic germinal centers are considered the main therapeutic targets. Well-controlled multicenter clinical trials are ongoing and data are awaited.

    更新日期:2017-06-21
  • Oral Combination Therapies for Hepatitis C Virus Infection: Successes, Challenges, and Unmet Needs
    Annu. Rev. Med. (IF 13.609) Pub Date : 2017-01-18
    Susanna Naggie, Andrew J. Muir

    The current standard of care for the treatment of hepatitis C virus (HCV) consists of interferon-free direct-acting antiviral (DAA) regimens, including combinations of DAAs and fixed-dose combination pills. DAAs for HCV are likely to be heralded as one of medicine's greatest advancements. Viral eradication rates are pushing 100% for many HCV-infected populations, including patients with HIV/HCV coinfection, decompensated cirrhosis, liver and kidney transplants, and end-stage liver disease. We highlight the greatest successes of combination DAA therapies, discuss the ongoing challenges, and identify the remaining patient subgroups with unmet medical needs.

    更新日期:2017-06-21
  • Ebola: Anatomy of an Epidemic
    Annu. Rev. Med. (IF 13.609) Pub Date : 2017-01-18
    Terrence Q. Lo, Barbara J. Marston, Benjamin A. Dahl, Kevin M. De Cock

    As of the end of March 2016, the West Africa epidemic of Ebola virus disease (Ebola) had resulted in a total of 28,646 cases, 11,323 of them fatal, reported to the World Health Organization. Guinea, Liberia, and Sierra Leone were most heavily affected, but Ebola cases were exported to several other African and European countries as well as the United States, with limited further transmission, including to healthcare workers. We review the descriptive epidemiology of the outbreak, novel aspects and insights concerning the unprecedented response, scientific observations, and public health implications. The large number of Ebola survivors has highlighted the frequency of persistent symptoms and the possibility of virus persistence in sanctuary sites, sometimes leading to delayed transmission. Although transmission appears to have ceased in 2016, the West Africa Ebola epidemic has profoundly influenced discussions and practice concerning global health security.

    更新日期:2017-06-21
  • Toward an Effective Ebola Virus Vaccine
    Annu. Rev. Med. (IF 13.609) Pub Date : 2017-01-18
    Rohan Keshwara, Reed F. Johnson, Matthias J. Schnell

    Long-term control of viral outbreaks requires the use of vaccines to impart acquired resistance and ensuing protection. In the wake of an epidemic, established immunity against a particular disease can limit spread and significantly decrease mortality. Creation of a safe and efficacious vaccine against Ebola virus (EBOV) has proven elusive so far, but various inventive strategies are now being employed to counteract the threat of outbreaks caused by EBOV and related filoviruses. Here, we present a current overview of progress in the field of Ebola virus vaccine development.

    更新日期:2017-06-21
  • Middle East Respiratory Syndrome: Emergence of a Pathogenic Human Coronavirus
    Annu. Rev. Med. (IF 13.609) Pub Date : 2017-01-18
    Anthony R. Fehr, Rudragouda Channappanavar, Stanley Perlman

    In 2012, a zoonotic coronavirus was identified as the causative agent of Middle East respiratory syndrome and was named MERS coronavirus (MERS-CoV). As of August 11, 2016, the virus has infected 1,791 patients, with a mortality rate of 35.6%. Although MERS-CoV generally causes subclinical or mild disease, infection can result in serious outcomes, including acute respiratory distress syndrome and multi-organ failure in patients with comorbidities. The virus is endemic in camels in the Arabian Peninsula and Africa and thus poses a consistent threat of frequent reintroduction into human populations. Disease prevalence will increase substantially if the virus mutates to increase human-to-human transmissibility. No therapeutics or vaccines are approved for MERS; thus, development of novel therapies is needed. Further, since many MERS cases are acquired in healthcare settings, public health measures and scrupulous attention to infection control are required to prevent additional MERS outbreaks.

    更新日期:2017-06-21
  • Gene Editing: A New Tool for Viral Disease
    Annu. Rev. Med. (IF 13.609) Pub Date : 2017-01-18
    Edward M. Kennedy, Bryan R. Cullen

    The emergence of the CRISPR/Cas system of antiviral adaptive immunity in bacteria as a facile system for gene editing in mammalian cells may well lead to gene editing becoming a novel treatment for a range of human diseases, especially those caused by deleterious germline mutations. Another potential target for gene editing are DNA viruses that cause chronic pathogenic diseases that cannot be cured by using currently available drugs. We review the current state of this field and discuss the potential advantages and problems with using a gene editing approach as a treatment for diseases caused by DNA viruses.

    更新日期:2017-06-21
  • Update on Alzheimer's Disease Therapy and Prevention Strategies
    Annu. Rev. Med. (IF 13.609) Pub Date : 2017-01-18
    W. Vallen Graham, Alessandra Bonito-Oliva, Thomas P. Sakmar

    Alzheimer's disease (AD) is the primary cause of age-related dementia. Effective strategies to prevent and treat AD remain elusive despite major efforts to understand its basic biology and clinical pathophysiology. Significant investments in therapeutic drug discovery programs over the past two decades have yielded some important insights but no blockbuster drugs to alter the course of disease. Because significant memory loss and cognitive decline are associated with neuron death and loss of gray matter, especially in the frontal cortex and hippocampus, some focus in drug development has shifted to early prevention of cellular pathology. Although clinical trial design is challenging, due in part to a lack of robust biomarkers with predictive value, some optimism has come from the identification and study of inherited forms of early-onset AD and genetic risk factors that provide insights about molecular pathophysiology and potential drug targets. In addition, better understanding of the Aβ amyloid pathway and the tau pathway—leading to amyloid plaques and neurofibrillary tangles, respectively, which are histopathological hallmarks of AD—continues to drive significant drug research and development programs. The main focus of this review is to summarize the most recent basic biology, biochemistry, and pharmacology that serve as a foundation for more than 50 active advanced-phase clinical trials for AD prevention and therapy.

    更新日期:2017-06-21
  • Mechanisms and Medicines for Remyelination
    Annu. Rev. Med. (IF 13.609) Pub Date : 2017-01-18
    Mark Bothwell

    Demyelination of central nervous system axons, associated with traumatic injury and demyelinating diseases such as multiple sclerosis, causes impaired neural transmission and ultimately axon degeneration. Consequently, extensive research has focused on signaling systems that promote myelinating activity of oligodendrocytes or promote production of new oligodendrocytes from oligodendrocyte progenitor cells. Many receptor systems, notably including growth factor receptors and G protein–coupled receptors, control myelination. A number of recent clinical trials target these receptor signaling pathways.

    更新日期:2017-06-21
  • Lysosomal Proteins as a Therapeutic Target in Neurodegeneration
    Annu. Rev. Med. (IF 13.609) Pub Date : 2017-01-18
    Jessica M. Mc Donald, Dimitri Krainc

    Several proteins that are mutated in lysosomal storage diseases are linked to neurodegenerative disease. This review focuses on some of these lysosomal enzymes and transporters, as well as current therapies that have emerged from the lysosomal storage disease field. Given the deeper genetic understanding of lysosomal defects in neurodegeneration, we explore why some of these orphan disease drug candidates are also attractive targets in subpopulations of individuals with neurodegenerative disease.

    更新日期:2017-06-21
  • Noninvasive Prenatal DNA Testing: The Vanguard of Genomic Medicine
    Annu. Rev. Med. (IF 13.609) Pub Date : 2017-01-18
    Lisa Hui, Diana W. Bianchi

    Noninvasive prenatal DNA testing is the vanguard of genomic medicine. In only four years, this screening test has revolutionized prenatal care globally and opened up new prospects for personalized medicine for the fetus. There are widespread implications for increasing the scope of human genetic variation that can be detected before birth, and for discovering more about maternofetal and placental biology. These include an urgent need to develop pretest education for all pregnant women and consistent post-test management recommendations for those with discordant test results. The reduction in invasive testing has had downstream effects on specialist training and caused many countries to re-examine their national approaches to prenatal screening. Finally, the accumulating datasets of genomic information on pregnant women and their fetuses raise ethical issues regarding consent for future data mining and intellectual property.

    更新日期:2017-06-21
Some contents have been Reproduced with permission of the American Chemical Society.
Some contents have been Reproduced by permission of The Royal Society of Chemistry.
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