American journal of respiratory and critical care medicine
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Am. J. Respir. Crit. Care Med. · May 2020
ReviewCystic Fibrosis: Emergence of Highly Effective Targeted Therapeutics and Potential Clinical Implications.
Cystic fibrosis (CF) remains the most common life-shortening hereditary disease in white populations, with high morbidity and mortality related to chronic airway mucus obstruction, inflammation, infection, and progressive lung damage. In 1989, the discovery that CF is caused by mutations in the CFTR (cystic fibrosis transmembrane conductance regulator) gene that encodes a cAMP-dependent anion channel vital for proper Cl- and HCO3- transport across epithelial surfaces provided a solid foundation for unraveling underlying disease mechanisms and the development of therapeutics targeting the basic defect in people with CF. ⋯ Furthermore, we review the path that led to the recent breakthrough in the development of highly effective CFTR-directed therapeutics, now applicable for up to 90% of people with CF who carry responsive CFTR mutations, including those with just a single copy of the most common F508del mutation. Finally, we discuss the remaining challenges and strategies to develop highly effective targeted therapies for all patients and the unprecedented potential of these novel therapies to transform CF from a fatal to a treatable chronic condition.
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Am. J. Respir. Crit. Care Med. · May 2020
A Human Lung Challenge Model to Evaluate the Safety and Immunogenicity of PPD and Live BCG.
Rationale: A human model to better understand tuberculosis immunopathogenesis and facilitate vaccine development is urgently needed. Objectives: We evaluated the feasibility, safety, and immunogenicity of live bacillus Calmette-Guérin (BCG) in a lung-oriented controlled human infection model. Methods: We recruited 106 healthy South African participants with varying degrees of tuberculosis susceptibility. ⋯ Immune responses were highly setting specific (in vitro vs. in vivo) and compartment specific (BAL vs. blood) and localized to the challenged lung segments. Conclusions: A lung-oriented mycobacterial controlled human infection model using live BCG and PPD is feasible and safe. These data inform the study of tuberculosis immunopathogenesis and strategies for evaluation and development of tuberculosis vaccine candidates.
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Am. J. Respir. Crit. Care Med. · May 2020
Practice GuidelineMaking Medical Treatment Decisions for Unrepresented Patients in the ICU. An Official American Thoracic Society/American Geriatrics Society Policy Statement.
Background and Rationale: ICU clinicians regularly care for patients who lack capacity, an applicable advance directive, and an available surrogate decision-maker. Although there is no consensus on terminology, we refer to these patients as "unrepresented." There is considerable controversy about how to make treatment decisions for these patients, and there is significant variability in both law and clinical practice. Purpose and Objectives: This multisociety statement provides clinicians and hospital administrators with recommendations for decision-making on behalf of unrepresented patients in the critical care setting. ⋯ These recommendations also are intended to strike an appropriate balance between excessive and insufficient procedural safeguards. The committee makes the following recommendations: 1) institutions should offer advance care planning to prevent patients at high risk for becoming unrepresented from meeting this definition; 2) institutions should implement strategies to determine whether seemingly unrepresented patients are actually unrepresented, including careful capacity assessments and diligent searches for potential surrogates; 3) institutions should manage decision-making for unrepresented patients using input from a diverse interprofessional, multidisciplinary committee rather than ad hoc by treating clinicians; 4) institutions should use all available information on the patient's preferences and values to guide treatment decisions; 5) institutions should manage decision-making for unrepresented patients using a fair process that comports with procedural due process; 6) institutions should employ this fair process even when state law authorizes procedures with less oversight. Conclusions: This multisociety statement provides guidance for clinicians and hospital administrators on medical decision-making for unrepresented patients in the critical care setting.