Investigating the Pathophysiology of Sepsis: Insights from Mechanistic and Animal Studies
Bibliographic record
Abstract
Sepsis is a life-threatening condition characterized by organ dysfunction due to an uncontrolled response to infection. Despite decades of research, the mortality rate remains high, emphasizing the need for an improved understanding of sepsis pathophysiology and improvements in preclinical animal research. Recently, extracellular histones, major mediators of organ dysfunction and death, have emerged as a potential therapeutic target for sepsis. In this thesis, we reported that the ability of heparin to neutralize the cytotoxic and procoagulant effects of histones is size-dependent but independent of the antithrombin- binding pentasaccharide. In contrast, the ability of heparin to neutralize histone-mediated impairment of activated protein C generation is independent of size and anticoagulant activity. These findings suggest that heparin variants may have differential therapeutic potential in vascular disease states that are associated with elevated levels of histones. Before testing the therapeutic efficacy of the heparin variants in vivo, we aimed to develop and standardize a murine model of sepsis that can be utilized in a multi-center platform. As one of the lead sites for the National Preclinical Sepsis Platform (NPSP), we optimized a 72-hour model of abdominal sepsis using supportive treatments. As sepsis predominately impacts the elderly, we also explored the impact of aging on the host response to sepsis using our fecal induced peritonitis (FIP) model. Aged FIP mice exhibited a higher mortality rate compared to young FIP mice. The worsened organ injury and poor survival in aged mice may be attributed to heightened inflammation in aged mice. We also observed trends in increased bacterial loads, increased coagulation, elevated cell free DNA, and decreased ADAMTS13 activity in aged septic mice. These findings help to improve our understanding of how aging impacts the host response to sepsis, which may be translated into therapeutic strategies that considers advanced age as a risk factor for sepsis.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.003 | 0.001 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.002 | 0.001 |
| Science and technology studies | 0.000 | 0.002 |
| Scholarly communication | 0.002 | 0.003 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.002 | 0.004 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".