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The requirement for antifungal susceptibility testing is increasing given the availability of new drugs, increasing populations of individuals at risk for fungal infection, and emerging multiresistant fungi. Rapid and accurate fungal identification remains at the forefront of laboratory efforts to guide empiric therapy. Antifungal susceptibility testing methods have greatly improved, but are subject to variation in results between methods. Careful standardization, validation, and extensive training of users is essential to ensure susceptibility results are clinically useful and interpreted appropriately. Interpretive criteria for many drugs and species are still lacking, but this will continue to evolve.Pathogenic fungi have several mechanisms of resistance to antifungal drugs, driven by the genetic plasticity and versatility of their homeostatic responses to stressful environmental cues. We critically review the molecular mechanisms of resistance and cellular adaptations of pathogenic fungi in response to antifungals and discuss the factors contributing to such resistance. We offer suggestions for the translational and clinical research agenda of this rapidly evolving and medically important field. A better understanding of antifungal resistance should assist in developing better detection tools and inform optimal strategies for preventing and treating refractory mycoses in the future.Various uncommon fungal pathogens have been increasingly identified as causes of disseminated and invasive fungal disease (IFD) worldwide. Growing recognition and clinical knowledge of these emerging fungal pathogens has occurred through improved molecular diagnostics, nucleic sequence databases, and taxonomic reclassification of medically significant fungi. However, emerging fungal diseases carry significant morbidity and mortality and, due to a paucity of published literature, the collective clinical experience with these fungi is often limited. In this review, we focus on unusual emerging fungal pathogens not extensively covered elsewhere in this issue of Infectious Diseases Clinics of North America.The breadth of fungi causing human disease and the spectrum of clinical presentations associated with these infections has widened. Epidemiologic trends display dramatic shifts with expanding geographic ranges, identification of new at-risk groups, increasing prevalence of resistant infections, and emergence of novel multidrug-resistant pathogenic fungi. Certain fungi have been transmitted between patients in clinical settings. selleck kinase inhibitor Major health events not typically associated with mycoses resulted in larger proportions of the population susceptible to secondary fungal infections. Many health care-related, environmental, and socioeconomic factors have influenced these epidemiologic shifts. This review summarizes updates to clinically significant fungal pathogens in North America.In this final of a 5-part Focus Seminar series on precision medicine, we focus on catecholaminergic polymorphic ventricular tachycardia (CPVT). This focus on CPVT allows us to take a "deep dive" and explore the full extent of the precision medicine opportunities for a single cardiovascular condition at a level that was not possible in the preceding articles. As a new paradigm presented in this article, it has become clear that CPVT can occur as either a typical or atypical form. Although there is a degree of overlap between the typical and atypical forms, it is notable that they arise due to different underlying genetic changes, likely exhibiting differing mechanisms of action, and presenting with different phenotypic features. The recognition of these differing forms of CPVT and their different etiologies and mechanisms is an important step toward implementing rapidly emerging precision medicine approaches that will tailor novel therapies to specific gene defects.In the initial 3 papers in this Focus Seminar series, the fundamentals and key concepts of precision medicine were reviewed, followed by a focus on precision medicine in the context of vascular disease and cardiomyopathy. For the remaining 2 papers, we focus on precision medicine in the context of arrhythmias. Specifically, in this fourth paper we focus on long QT syndrome, Brugada syndrome, and atrial fibrillation. The final (fifth) paper will deal with catecholaminergic polymorphic ventricular tachycardia. These arrhythmias represent a spectrum of disease ranging from common to relatively rare, with very different genetic and environmental causative factors, and with differing clinical manifestations that range from almost no consequences to lethality in childhood or adolescence if untreated. Accordingly, the emerging precision medicine approaches to these arrhythmias vary significantly, but several common themes include increased use of genetic testing, avoidance of triggers, and personalized risk stratification to guide the use of arrhythmia-specific therapies.Inherited cardiomyopathies are commonly occurring myocardial disorders that are associated with substantial morbidity and mortality. Clinical management strategies have focused on treatment of heart failure and arrhythmic complications in symptomatic patients according to standardized guidelines. Clinicians are now being urged to implement precision medicine, but what does this involve? Advances in understanding of the genetic underpinnings of inherited cardiomyopathies have brought new possibilities for interventions that are tailored to genes, specific variants, or downstream mechanisms. However, the phenotypic variability that can occur with any given pathogenic variant suggests that factors other than single driver gene mutations are often involved. This is propelling a new imperative to elucidate the nuanced ways in which individual combinations of genetic variation, comorbidities, and lifestyle may influence cardiomyopathy phenotypes. Here, Part 3 of a 5-part precision medicine Focus Seminar series reviews the current status and future opportunities for precision medicine in the inherited cardiomyopathies.In this second of a 5-part Focus Seminar series, we focus on precision medicine in the context of vascular disease. The most common vascular disease worldwide is atherosclerosis, which is the primary cause of coronary artery disease, peripheral vascular disease, and a large proportion of strokes and other disorders. Atherosclerosis is a complex genetic disease that likely involves many hundreds to thousands of single nucleotide polymorphisms, each with a relatively modest effect for causing disease. Conversely, although less prevalent, there are many vascular disorders that typically involve only a single genetic change, but these changes can often have a profound effect that is sufficient to cause disease. These are termed "Mendelian vascular diseases," which include Marfan and Loeys-Dietz syndromes. Given the very different genetic basis of atherosclerosis versus Mendelian vascular diseases, this article was divided into 2 parts to cover the most promising precision medicine approaches for these disease types.
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