Rationale: The contributions of diverse cell populations in the human lung to pulmonary fibrosis pathogenesis are poorly understood. Single-cell RNA sequencing can reveal changes within individual cell populations during pulmonary fibrosis that are important for disease pathogenesis. Objectives: To determine whether single-cell RNA sequencing can reveal disease-related heterogeneity within alveolar macrophages, epithelial cells, or other cell types in lung tissue from subjects with pulmonary fibrosis compared with control subjects. Methods: We performed single-cell RNA sequencing on lung tissue obtained from eight transplant donors and eight recipients with pulmonary fibrosis and on one bronchoscopic cryobiospy sample from a patient with idiopathic pulmonary fibrosis. We validated these data using in situ RNA hybridization, immunohistochemistry, and bulk RNA-sequencing on flow-sorted cells from 22 additional subjects. Measurements and Main Results: We identified a distinct, novel population of profibrotic alveolar macrophages exclusively in patients with fibrosis. Within epithelial cells, the expression of genes involved in Wnt secretion and response was restricted to nonoverlapping cells. We identified rare cell populations including airway stem cells and senescent cells emerging during pulmonary fibrosis. We developed a web-based tool to explore these data. Conclusions: We generated a single-cell atlas of pulmonary fibrosis. Using this atlas, we demonstrated heterogeneity within alveolar macrophages and epithelial cells from subjects with pulmonary fibrosis. These results support the feasibility of discovery-based approaches using next-generation sequencing technologies to identify signaling pathways for targeting in the development of personalized therapies for patients with pulmonary fibrosis.

Rationale: The identification of informative elements of the host response to infection may improve the diagnosis and management of bacterial pneumonia.Objectives: To determine whether the absence of alveolar neutrophilia can exclude bacterial pneumonia in critically ill patients with suspected infection and to test whether signatures of bacterial pneumonia can be identified in the alveolar macrophage transcriptome.Methods: We determined the test characteristics of alveolar neutrophilia for the diagnosis of bacterial pneumonia in three cohorts of mechanically ventilated patients. In one cohort, we also isolated macrophages from alveolar lavage fluid and used the transcriptome to identify signatures of bacterial pneumonia. Finally, we developed a humanized mouse model of Pseudomonas aeruginosa pneumonia to determine if pathogen-specific signatures can be identified in human alveolar macrophages.Measurements and Main Results: An alveolar neutrophil percentage less than 50% had a negative predictive value of greater than 90% for bacterial pneumonia in both the retrospective (n = 851) and validation cohorts (n = 76 and n = 79). A transcriptional signature of bacterial pneumonia was present in both resident and recruited macrophages. Gene signatures from both cell types identified patients with bacterial pneumonia with test characteristics similar to alveolar neutrophilia. Conclusions:The absence of alveolar neutrophilia has a high negative predictive value for bacterial pneumonia in critically ill patients with suspected infection. Macrophages can be isolated from alveolar lavage fluid obtained during routine care and used for RNA-Seq analysis. This novel approach may facilitate a longitudinal and multidimensional assessment of the host response to bacterial pneumonia.

Objective: This study examined the associations between edentulism, dental care service utilization, and cognitive functioning trajectories among older adults. Method: Longitudinal data from the Health and Retirement Study (2006-2014) were employed to examine individuals aged 51 and older who were identified as having normal cognition at baseline ( N = 12,405). Cognitive functioning was measured with a modified version of the Telephone Interview for Cognition Status. Edentulism was self-reported as total tooth loss at baseline. Dental care service utilization was measured by self-report of having visited a dentist at least once during the previous 2 years. Results: The results indicated that edentulism and dental care service utilization were independently associated with cognitive decline during the observation period. Findings also showed that dental care service utilization moderated the association between edentulism and cognitive decline. Discussion: The findings suggested that providing access to dental services may promote cognitive health and potentially reduce health care expenditures.

Background and Objectives This study investigated the relationship between childhood friendships and cognitive functioning, as assessed with cognitive status and decline among adults aged 45 and older in China. We also examined the mediating effect of adult social disconnectedness and adult loneliness for this relationship. Research Design and Methods This study was based on 3 waves of data from the China Health and Retirement Longitudinal Study (CHARLS; 2011, 2013, 2015; N = 13,959). Cognitive functioning was assessed with episodic memory. Childhood friendship measures were taken from the 2014 life history module of the CHARLS. Two dimensions of adult social isolation, loneliness and social disconnectedness, were included as mediators. Latent growth curve modeling was utilized to test the associations between childhood friendships, adult social isolation, and cognitive functioning. Results Adverse childhood friendship experiences were found to be significantly associated with both lower initial cognitive status and the rate of decline in cognitive functioning. Our findings indicated that adult loneliness and social disconnectedness partly mediated the link between childhood friendship experiences and the initial level of cognitive functioning, but not cognitive decline later in life. Discussion and Implications The findings emphasized the enduring importance of childhood friendships for cognitive functioning later in life. Interventions that focus on improving social participation through fostering friendships in childhood may have long-term benefits for cognition later in life.