Retrospective cohort study comparing two versus three blood culture sets in people who inject drugs.

BACKGROUND: The current standard of drawing two vs three blood culture sets lacks adequate guidance. Because people who inject drugs are at higher risk for bacteraemia and life-threatening infection, consideration of a third blood culture becomes more important. AIM: To investigate the risks and benefits of obtaining two versus three blood culture sets. METHODS: Retrospective cohort study of adults who inject drugs at a multicentre catch-net hospital system from 2017-2022. FINDINGS: 998 people who inject drugs and 2278 blood culture sets were analysed. There were 1618 episodes with two blood culture sets and 660 episodes with three. A potential benefit of adding a third blood culture was seen in 30 (4.5%) episodes. However, only 13 (2.0%) episodes showed pathogen-identifying benefit, as 17 (2.6%) involved known inadequately treated infections or the same pathogen in another culture. The number of blood culture sets needed to achieve diagnostic benefit was 51. There were more contaminants for three blood culture sets (65, 9.8%) than for two (114, 7.0%) (p < 0.00001). By adding a third blood culture, the risk of a contaminant increased by 39.7%; the number of blood culture sets needed to find a contaminant was 36. Of 122 episodes with only contaminants and available for analysis, 111 (91.0%) experienced at least one complication. 33 (27.0%) patients experienced either prolonged admission, readmission, or unnecessary antibiotic administration. CONCLUSIONS: The benefits of possibly isolating a pathogen from a third blood culture set do not universally outweigh the risks for contaminant growth for people who inject drugs. A third blood culture should be considered in specific clinical scenarios (i.e. inadequately treated endocarditis and osteomyelitis).

Transcriptional control of subtype switching ensures adaptation and growth of pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDA) is a heterogeneous disease comprised of a basal-like subtype with mesenchymal gene signatures, undifferentiated histopathology and worse prognosis compared to the classical subtype. Despite their prognostic and therapeutic value, the key drivers that establish and control subtype identity remain unknown. Here, we demonstrate that PDA subtypes are not permanently encoded, and identify the GLI2 transcription factor as a master regulator of subtype inter-conversion. GLI2 is elevated in basal-like PDA lines and patient specimens, and forced GLI2 activation is sufficient to convert classical PDA cells to basal-like. Mechanistically, GLI2 upregulates expression of the pro-tumorigenic secreted protein, Osteopontin (OPN), which is especially critical for metastatic growth in vivo and adaptation to oncogenic KRAS ablation. Accordingly, elevated GLI2 and OPN levels predict shortened overall survival of PDA patients. Thus, the GLI2-OPN circuit is a driver of PDA cell plasticity that establishes and maintains an aggressive variant of this disease.