Daily Respiratory Research Analysis

Physicians in critical care settings face information overload and decision fatigue, contributing to under-recognition of acute respiratory distress syndrome, which affects over 10% of intensive care patients and carries over 40% mortality rate. We present a reproducible computational pipeline to automatically identify this condition retrospectively in mechanically ventilated adults. This computational pipeline operationalizes the Berlin Definition by detecting bilateral infiltrates from radiology reports and a pneumonia diagnosis from attending physician notes, using interpretable classifiers trained on labeled data. Here we show that our integrated pipeline achieves high performance-93.5% sensitivity and 17.4% false positive rate-when applied to a held-out and publicly-available dataset from an external hospital. This substantially exceeds the 22.6% documentation rate observed in the same cohort. These results demonstrate that our automated adjudication pipeline can accurately identify an under-diagnosed condition in critical care and may support timely recognition and intervention through integration with electronic health records.

Bacteria evolving within human hosts encounter selective tradeoffs that render mutations adaptive in one context and deleterious in another. Here, we report that the cystic fibrosis-associated pathogen Burkholderia dolosa overcomes in-human selective tradeoffs by acquiring successive point mutations that alternate phenotypes. We sequenced the whole genomes of 931 respiratory isolates from two recently infected cystic fibrosis patients and an epidemiologically-linked, chronically-infected patient. These isolates are contextualized using 112 historical genomes from the same outbreak strain. Within both newly infected patients, convergent mutations that disrupt O-antigen expression quickly arose, comprising 29% and 63% of their B. dolosa communities by 3 years. The selection for loss of O-antigen starkly contrasts with our previous observation of parallel O-antigen-restoring mutations after many years of chronic infection in the historical outbreak. Experimental characterization reveals that O-antigen loss increases uptake in immune cells while decreasing competitiveness in the mouse lung. We propose that the balance of these pressures, and thus whether O-antigen expression is advantageous, depends on tissue localization and infection duration. These results suggest that mutation-driven phenotypic alternation may be underestimated without dense temporal sampling, particularly for microbes with prolonged infection or colonization.

Multidrug-resistant (MDR) bacterial pneumonia poses a critical threat to global public health. The opportunistic Gram-negative pathogen Pseudomonas aeruginosa is a leading cause of nosocomial-associated pneumonia, and an effective vaccine could protect vulnerable populations, including the elderly, immunocompromised, and those with chronic respiratory diseases. Highly heterogeneous outer membrane vesicles (OMVs), shed from Gram-negative bacteria, are studded with immunogenic lipids, proteins, and virulence factors. To overcome limitations in OMV stability and consistency, we described what we believe to be a novel vaccine platform that combines immunogenic OMVs with precision nanotechnology - creating a bacterial cellular nanoparticle (CNP) vaccine candidate, termed Pa-STING CNP, which incorporates an adjuvanted core that activates the STING (stimulator of interferon genes) pathway. In this design, OMVs are coated onto the surface of self-adjuvanted STING nanocores. Pa-STING CNP vaccination induced substantial antigen presenting cell recruitment and activation in draining lymph nodes, robust anti-Pseudomonas antibody responses, and provided protection against lethal challenge with the hypervirulent clinical P. aeruginosa isolate PA14. Antibody responses mediated this protection and provided passive immunity against the heterologous P. aeruginosa strain PA01. These findings provided evidence that nanotechnology can be used to create a highly efficacious vaccine platform against high priority MDR pathogens such as P. aeruginosa.