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Annual Review of Medicine - Volume 70, 2019
Volume 70, 2019
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Arrhythmogenic Right Ventricular Cardiomyopathy: Progress Toward Personalized Management
Vol. 70 (2019), pp. 1–18More LessArrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited heart disease characterized by fibrofatty replacement of the ventricular myocardium, a high risk of ventricular arrhythmias, and progressive ventricular dysfunction. The clinical course is highly variable, and optimal approaches to management remain undefined. ARVC is associated with pathogenic variants in genes encoding the cardiac desmosome. Genetic testing facilitates identification of at-risk family members, but penetrance of ARVC in pathogenic variant carriers is difficult to predict. Participation in endurance exercise is a known key risk factor. However, there remains significant uncertainty about which family member will develop disease and how best to approach longitudinal screening. Our clinically focused review describes how new insights gained from natural history studies, improved understanding of pathogenic mechanisms, and appreciation of genetic and environmental modifiers have set the stage for developing personalized approaches to managing both ARVC patients and their at-risk family members.
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Capitalizing on Insights from Human Genetics to Identify Novel Therapeutic Targets for Coronary Artery Disease
Vol. 70 (2019), pp. 19–32More LessCoronary artery disease (CAD) is a major cause of morbidity and mortality. Unfortunately, despite decades of research focused on disease pathogenesis, we still lack a sufficient pharmacopeia for preventing CAD. The failure of many novel cardiovascular drugs to improve clinical outcomes reflects the major substantial challenge of drug development: identifying causal mechanisms that can be therapeutically manipulated to lower disease risk. Identifying genetic variants that are associated with risk of CAD has emerged as a clear path toward improving our understanding of the underlying mechanisms that lead to disease and to the development of new therapies. Here, we review the potential utility and limitations of using human genetics to guide the identification of therapeutic targets for CAD.
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Innovations in Ventricular Assist Devices for End-Stage Heart Failure
Vol. 70 (2019), pp. 33–44More LessThe number of patients with end-stage heart failure (HF) continues to increase over time, but there has been little change in the availability of organs for cardiac transplantation, intensifying the demand for left ventricular assist devices (LVADs) as a bridge to transplantation. There is also a growing number of patients with end-stage HF who are not transplant candidates but may be eligible for long-term support with an LVAD, known as destination therapy. Due to this increasing demand, LVAD technology has evolved, resulting in transformative improvements in outcomes. Additionally, with growing clinical experience patient management continues to be refined, leading to iterative improvements in outcomes. With outcomes continuing to improve, the potential benefit from LVAD therapy is being considered for patients earlier in their course of advanced HF. We review recent changes in technology, patient management, and implant decision making in LVAD therapy.
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New and Emerging Therapies for Pulmonary Arterial Hypertension
Vol. 70 (2019), pp. 45–59More LessPulmonary arterial hypertension (PAH) is a pulmonary vasculopathy that causes right ventricular dysfunction and exercise limitation and progresses to death. New findings from translational studies have suggested alternative pathways for treatment. These avenues include sex hormones, genetic abnormalities and DNA damage, elastase inhibition, metabolic dysfunction, cellular therapies, and anti-inflammatory approaches. Both novel and repurposed compounds with rationale from preclinical experimental models and human cells are now in clinical trials in patients with PAH. Findings from these studies will elucidate the pathobiology of PAH and may result in clinically important improvements in outcome.
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Non–Vitamin K Antagonist Oral Anticoagulants in the Treatment of Atrial Fibrillation
Vol. 70 (2019), pp. 61–75More LessAtrial fibrillation (AF) increases a patient's stroke risk four- to five-fold. Anticoagulation with the vitamin K antagonist (VKA) warfarin reduces the risk of stroke by 67%, but warfarin carries a significant risk of major bleeding and has unpredictable pharmacodynamics with a narrow therapeutic window, necessitating frequent monitoring of its anticoagulant effect. The non–vitamin K antagonist oral anticoagulants (NOACs) dabigatran, rivaroxaban, apixaban, and edoxaban provide more predictable anticoagulant activity than warfarin with a lower risk of major bleeding, and each is noninferior to warfarin for the prevention of stroke. All have earned regulatory approval in the past eight years. At least one of the NOACs is approved for use in all patients with AF, except those with mechanical valves and rheumatic mitral valve disease, for whom warfarin remains the only option. Recent clinical trials have shown that antithrombotic regimens including NOACs are safe and effective in patients with AF who need potent antiplatelet therapy.
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Molecular Diagnostics for Mycobacterium tuberculosis Infection
Vol. 70 (2019), pp. 77–90More LessResistance to antimycobacterial drugs is a major barrier to effective treatment of Mycobacterium tuberculosis infection. Molecular diagnostic techniques based on the association between specific gene mutations and phenotypic resistance to certain drugs offer the opportunity to rapidly ascertain whether drug resistance is present and to alter treatment before further resistance develops. Current barriers to successful implementation of rapid diagnostics include imperfect knowledge regarding the full spectrum of mutations associated with resistance, limited utilization of molecular diagnostics where they are most needed, and the requirement for specialized laboratory facilities to perform molecular testing. Further understanding of genotypic–phenotypic correlates of resistance and streamlined implementation platforms will be necessary to optimize the public health impact of molecular resistance testing for M. tuberculosis.
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Structure-Based Vaccine Antigen Design
Vol. 70 (2019), pp. 91–104More LessEnabled by new approaches for rapid identification and selection of human monoclonal antibodies, atomic-level structural information for viral surface proteins, and capacity for precision engineering of protein immunogens and self-assembling nanoparticles, a new era of antigen design and display options has evolved. While HIV-1 vaccine development has been a driving force behind these technologies and concepts, clinical proof-of-concept for structure-based vaccine design may first be achieved for respiratory syncytial virus (RSV), where conformation-dependent access to neutralization-sensitive epitopes on the fusion glycoprotein determines the capacity to induce potent neutralizing activity. Success with RSV has motivated structure-based stabilization of other class I viral fusion proteins for use as immunogens and demonstrated the importance of structural information for developing vaccines against other viral pathogens, particularly difficult targets that have resisted prior vaccine development efforts. Solving viral surface protein structures also supports rapid vaccine antigen design and application of platform manufacturing approaches for emerging pathogens.
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The Global Landscape of Tuberculosis Therapeutics
Vol. 70 (2019), pp. 105–120More LessTuberculosis (TB) is one of the oldest infections afflicting humans yet remains the number one infectious disease killer worldwide. Despite decades of experience treating this disease, TB regimens require months of multidrug therapy, even for latent infections. There have been important recent advances in treatment options across the spectrum of TB, from latent infection to extensively drug-resistant (XDR) TB disease. In addition, new, potent drugs are emerging out of the development pipeline and are being tested in novel regimens in multiple currently enrolling trials. Shorter, safer regimens for many forms of TB are now available or are in our near-term vision. We review recent advances in TB therapeutics and provide an overview of the upcoming clinical trials landscape that will help define the future of worldwide TB treatment.
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Zika Virus Vaccine Development: Progress in the Face of New Challenges
Vol. 70 (2019), pp. 121–135More LessZika virus (ZIKV) emerged at a global level when it spread to the Americas and began causing congenital malformations and microcephaly in 2015. A rapid response by academia, government, public health infrastructure, and industry has enabled the expedited development and testing of a suite of vaccine platforms aiming to control and eliminate ZIKV-induced disease. Analysis of key immunization and pathogenesis studies in multiple animal models, including during pregnancy, has begun to define immune correlates of protection. Nonetheless, the deployment of ZIKV vaccines, along with the confirmation of their safety and efficacy, still has major challenges, one of which is related to the waning of the epidemic. In this review, we discuss the measures that enabled rapid progress and highlight the path forward for successful deployment of ZIKV vaccines.
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Long-Acting HIV Drugs for Treatment and Prevention
Vol. 70 (2019), pp. 137–150More LessAntiretroviral drugs have revolutionized the treatment and prevention of HIV infection; however, adherence is critical for sustained efficacy. Current HIV treatment consists of three-drug regimens, and current HIV pre-exposure prophylaxis (PrEP) consists of a two-drug regimen; both generally require adherence to once-daily dosing. Long-acting formulations are useful in the treatment and prevention of other conditions (e.g., contraceptives, antipsychotics) and help promote adherence. Newer long-acting formulations of approved and investigational antiretroviral drugs in existing and newer mechanistic classes are under study for HIV treatment and prevention, including some phase III trials. Although long-acting antiretroviral drugs hold promise, some clinical challenges exist, including managing side effects, drug-drug interactions, pregnancy, and long-lasting drug concentrations that could lead to the development of drug resistance. This review aims to summarize currently available information on long-acting antiretroviral drugs for HIV treatment and prevention.
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DNA Methylation and Susceptibility to Autism Spectrum Disorder
Vol. 70 (2019), pp. 151–166More LessThe prevalence of autism spectrum disorder (ASD) has been increasing steadily over the last 20 years; however, the molecular basis for the majority of ASD cases remains unknown. Recent advances in next-generation sequencing and detection of DNA modifications have made methylation-dependent regulation of transcription an attractive hypothesis for being a causative factor in ASD etiology. Evidence for abnormal DNA methylation in ASD can be seen on multiple levels, from genetic mutations in epigenetic machinery to loci-specific and genome-wide changes in DNA methylation. Epimutations in DNA methylation can be acquired throughout life, as global DNA methylation reprogramming is dynamic during embryonic development and the early postnatal period that corresponds to the peak time of synaptogenesis. However, technical advances and causative evidence still need to be established before abnormal DNA methylation and ASD can be confidently associated.
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Metformin for Treatment of Fragile X Syndrome and Other Neurological Disorders
Vol. 70 (2019), pp. 167–181More LessFragile X syndrome (FXS) is the most frequent inherited form of intellectual disability and autism spectrum disorder. Loss of the fragile X mental retardation protein, FMRP, engenders molecular, behavioral, and cognitive deficits in FXS patients. Experiments using different animal models advanced our knowledge of the pathophysiology of FXS and led to the discovery of many targets for drug treatments. In this review, we discuss the potential of metformin, an antidiabetic drug approved by the US Food and Drug Administration, to correct core symptoms of FXS and other neurological disorders in humans. We summarize its mechanisms of action in different animal and cellular models and human diseases.
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Postpartum Depression: Pathophysiology, Treatment, and Emerging Therapeutics
Vol. 70 (2019), pp. 183–196More LessPostpartum depression (PPD) is common, disabling, and treatable. The strongest risk factor is a history of mood or anxiety disorder, especially having active symptoms during pregnancy. As PPD is one of the most common complications of childbirth, it is vital to identify best treatments for optimal maternal, infant, and family outcomes. New understanding of PPD pathophysiology and emerging therapeutics offer the potential for new ways to add to current medications, somatic treatments, and evidence-based psychotherapy. The benefits and potential harms of treatment, including during breastfeeding, are presented.
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Cystic Fibrosis: Emerging Understanding and Therapies
Vol. 70 (2019), pp. 197–210More LessCystic fibrosis (CF) is the most common life-limiting genetic disease in Caucasian patients. Continued advances have led to improved survival, and adults with CF now outnumber children. As our understanding of the disease improves, new therapies have emerged that improve the basic defect, enabling patient-specific treatment and improved outcomes. However, recurrent exacerbations continue to lead to morbidity and mortality, and new pathogens have been identified that may lead to worse outcomes. In addition, new complications, such as CF-related diabetes and increased risk of gastrointestinal cancers, are creating new challenges in management. For patients with end-stage disease, lung transplantation has remained one of the few treatment options, but challenges in identifying the most appropriate patients remain.
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Progress in Understanding and Treating Idiopathic Pulmonary Fibrosis
Vol. 70 (2019), pp. 211–224More LessThis is a time of substantial progress in the evaluation and care of patients with idiopathic pulmonary fibrosis (IPF). In addition to the approval and widespread availability of the first IPF-specific therapies, there have been improvements in imaging interpretation and lung biopsy methods to enable more expeditious and more accurate diagnosis. Recent advances in identifying genetic factors that underlie susceptibility to IPF and affect prognosis have raised the possibility of personalized therapeutic approaches in the future. Further, evolving work is elucidating novel mechanisms influencing epithelial, mesenchymal, and inflammatory cell responses during the injury-repair process, thus advancing understanding of disease pathogenesis. As analytic approaches mature, the field is now poised to harness the power of rapidly advancing “omics” technologies to further accelerate progress.
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Current Status of Living Donor Liver Transplantation in the United States
Vol. 70 (2019), pp. 225–238More LessAdult-to-adult living donor liver transplantation (LDLT) was introduced in response to the shortage of deceased donor liver grafts. The number of adult living donor transplants is increasing due to improved outcomes and increasing need. Advantages of LDLT include optimization of the timing of transplant, better organ quality, and lower rates of recipient mortality compared to staying on the wait list for deceased donor liver transplant. Donor safety remains the major focus when considering LDLT. Recent advancements have supported the increased use of LDLT to help decrease wait list death and improve long-term survival of transplant recipients.
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CRISPR Correction of Duchenne Muscular Dystrophy
Vol. 70 (2019), pp. 239–255More LessThe ability to efficiently modify the genome using CRISPR technology has rapidly revolutionized biology and genetics and will soon transform medicine. Duchenne muscular dystrophy (DMD) represents one of the first monogenic disorders that has been investigated with respect to CRISPR-mediated correction of causal genetic mutations. DMD results from mutations in the gene encoding dystrophin, a scaffolding protein that maintains the integrity of striated muscles. Thousands of different dystrophin mutations have been identified in DMD patients, who suffer from a loss of ambulation followed by respiratory insufficiency, heart failure, and death by the third decade of life. Using CRISPR to bypass DMD mutations, dystrophin expression has been efficiently restored in human cells and mouse models of DMD. Here, we review recent progress toward the development of possible CRISPR therapies for DMD and highlight opportunities and potential obstacles in attaining this goal.
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Emerging Genetic Therapy for Sickle Cell Disease
Vol. 70 (2019), pp. 257–271More LessThe genetic basis of sickle cell disease (SCD) was elucidated >60 years ago, yet current therapy does not rely on this knowledge. Recent advances raise prospects for improved, and perhaps curative, treatment. First, transcription factors, BCL11A and LRF/ZBTB7A, that mediate silencing of the β-like fetal (γ-) globin gene after birth have been identified and demonstrated to act at the γ-globin promoters, precisely at recognition sequences disrupted in rare individuals with hereditary persistence of fetal hemoglobin. Second, transformative advances in gene editing and progress in lentiviral gene therapy provide diverse opportunities for genetic strategies to cure SCD. Approaches include hematopoietic gene therapy by globin gene addition, gene editing to correct the SCD mutation, and genetic manipulations to enhance fetal hemoglobin production, a potent modifier of the clinical phenotype. Clinical trials may soon identify efficacious and safe genetic approaches to the ultimate goal of cure for SCD.
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Entering the Modern Era of Gene Therapy
Vol. 70 (2019), pp. 273–288More LessGene therapies are gaining momentum as promising early successes in clinical studies accumulate and examples of regulatory approval for licensing increase. Investigators are advancing with cautious optimism that effective, durable, and safe therapies will provide benefit to patients—not only those with single-gene disorders but those with complex acquired diseases as well. While the strategies being translated from the lab to the clinic are numerous, this review focuses on the clinical research that has forged the gene therapy field as it currently stands.
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Ethics of Human Genome Editing
Vol. 70 (2019), pp. 289–305More LessAdvances in human genome editing, in particular the development of the clustered regularly interspaced palindromic repeats (CRISPR)/Cas9 method, have led to increasing concerns about the ethics of editing the human genome. In response, the US National Academy of Sciences and the National Academy of Medicine constituted a multidisciplinary, international committee to review the current status and make recommendations. I was a member of that committee, and the core of this review reflects the committee's conclusions. The committee's report, issued in February 2017, recommends the application of current ethical and regulatory standards for gene therapy to somatic (nonheritable) human genome editing. It also recommends allowing experimental germline genome editing to proceed if (a) it is restricted to preventing transmission of a serious disease or condition, (b) the edit is a modification to a common DNA sequence known not to be associated with disease, and (c) the research is conducted under a stringent set of ethical and regulatory requirements. Crossing the so-called red line of germline genome editing raises important bioethical issues, most importantly, serious concern about the potential negative impact on individuals with disabilities. This review highlights some of the major ethical considerations in human genome editing in light of the report's recommendations.
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Previous Volumes
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Volume 76 (2025)
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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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Volume 62 (2011)
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Volume 61 (2010)
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Volume 60 (2009)
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Volume 59 (2008)
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Volume 58 (2007)
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Volume 57 (2006)
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Volume 56 (2005)
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Volume 55 (2004)
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Volume 54 (2003)
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Volume 53 (2002)
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Volume 52 (2001)
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Volume 51 (2000)
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Volume 50 (1999)
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Volume 49 (1998)
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Volume 48 (1997)
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Volume 47 (1996)
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Volume 46 (1995)
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Volume 45 (1994)
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Volume 44 (1993)
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Volume 43 (1992)
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Volume 42 (1991)
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Volume 41 (1990)
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Volume 40 (1989)
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Volume 39 (1988)
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Volume 38 (1987)
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Volume 37 (1986)
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Volume 36 (1985)
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Volume 35 (1984)
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Volume 34 (1983)
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Volume 33 (1982)
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Volume 32 (1981)
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Volume 31 (1980)
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Volume 30 (1979)
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Volume 29 (1978)
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Volume 28 (1977)
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Volume 27 (1976)
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Volume 26 (1975)
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Volume 25 (1974)
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Volume 24 (1973)
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Volume 23 (1972)
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Volume 22 (1971)
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Volume 21 (1970)
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Volume 20 (1969)
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Volume 19 (1968)
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Volume 18 (1967)
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Volume 17 (1966)
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Volume 16 (1965)
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Volume 15 (1964)
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Volume 14 (1963)
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Volume 13 (1962)
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Volume 12 (1961)
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Volume 11 (1960)
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Volume 10 (1959)
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Volume 9 (1958)
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Volume 8 (1957)
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Volume 7 (1956)
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Volume 6 (1955)
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Volume 5 (1954)
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Volume 4 (1953)
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Volume 3 (1952)
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Volume 2 (1951)
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Volume 1 (1950)
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Volume 0 (1932)