Integrative Transcriptome Analyses of the Human Fallopian Tube: Fimbria and Ampulla-Site of Origin of Serous Carcinoma of the Ovary.

Epithelial ovarian cancer represents a group of heterogeneous diseases with high grade serous cancer (HGSC) representing the most common histotype. Molecular profiles of precancerous lesions found in the fallopian tube have implicated this tissue as the presumptive site of origin of HGSC. Precancerous lesions are primarily found in the distal fallopian tube (fimbria), near the ovary relative to the proximal tissue (ampulla), nearer to the uterus. The proximity of the fimbria to the ovary and the link between ovulation, through follicular fluid release, and ovarian cancer risk led us to examine transcriptional responses of fallopian tube epithelia (FTE) at the different anatomical sites of the human fallopian tube. Gene expression profiles of matched FTE from the fimbria and from premenopausal women resulted in differentially expressed genes (DEGs): CYYR1, SALL1, FOXP2, TAAR1, AKR1C2/C3/C4, NMBR, ME1 and GSTA2. These genes are part of the antioxidant, stem and inflammation pathways. Comparisons between the luteal phase (post-ovulation) to the follicular phase (pre-ovulation) demonstrated greater differences in DEGs than a comparison between fimbria and fallopian tube anatomical differences alone. This data suggests that cyclical transcriptional changes experienced in pre-menopause are inherent physiological triggers that expose the FTE in the fimbria to cytotoxic stressors. These cyclical exposures induce transcriptional changes reflective of genotoxic and cytotoxic damage to the FTE in the fimbria which are closely related to transcriptional and genomic alterations observed in ovarian cancer.

Improving situation awareness to reduce unrecognized clinical deterioration and serious safety events.

BACKGROUND AND OBJECTIVE: Failure to recognize and treat clinical deterioration remains a source of serious preventable harm for hospitalized patients. We designed a system to identify, mitigate, and escalate patient risk by using principles of high-reliability organizations. We hypothesized that our novel care system would decrease transfers determined to be unrecognized situation awareness failures events (UNSAFE). These were defined as any transfer from an acute care floor to an ICU where the patient received intubation, inotropes, or ≥ 3 fluid boluses in first hour after arrival or before transfer. METHODS: The setting for our observational time series study was a quaternary care children's hospital. Before initiating tests of change, 2 investigators reviewed recent serious safety events (SSEs) and floor-to-ICU transfers. Collectively, 5 risk factors were associated with each event: family concerns, high-risk therapies, presence of an elevated early warning score, watcher/clinician gut feeling, and communication concerns. Using the model for improvement, an intervention was developed and tested to reliably and proactively identify patient risk and mitigate that risk through unit-based huddles. A 3-times daily inpatient huddle was added to ensure risks were escalated and addressed. Later, a "robust" and explicit plan for at-risk patients was developed and spread. RESULTS: The rate of UNSAFE transfers per 10,000 non-ICU inpatient days was significantly reduced from 4.4 to 2.4 over the study period. The days between inpatient SSEs also increased significantly. CONCLUSIONS: A reliable system to identify, mitigate, and escalate risk was associated with a near 50% reduction in UNSAFE transfers and SSEs.