21 research outputs found
An immune dysfunction score for stratification of patients with acute infection based on whole-blood gene expression
Dysregulated host responses to infection can lead to organ dysfunction and sepsis, causing millions of global deaths each year. To alleviate this burden, improved prognostication and biomarkers of response are urgently needed. We investigated the use of whole-blood transcriptomics for stratification of patients with severe infection by integrating data from 3149 samples from patients with sepsis due to community-acquired pneumonia or fecal peritonitis admitted to intensive care and healthy individuals into a gene expression reference map. We used this map to derive a quantitative sepsis response signature (SRSq) score reflective of immune dysfunction and predictive of clinical outcomes, which can be estimated using a 7- or 12-gene signature. Last, we built a machine learning framework, SepstratifieR, to deploy SRSq in adult and pediatric bacterial and viral sepsis, H1N1 influenza, and COVID-19, demonstrating clinically relevant stratification across diseases and revealing some of the physiological alterations linking immune dysregulation to mortality. Our method enables early identification of individuals with dysfunctional immune profiles, bringing us closer to precision medicine in infection.peer-reviewe
Increasing frailty is associated with higher prevalence and reduced recognition of delirium in older hospitalised inpatients: results of a multi-centre study
Purpose:
Delirium is a neuropsychiatric disorder delineated by an acute change in cognition, attention, and consciousness. It is common, particularly in older adults, but poorly recognised. Frailty is the accumulation of deficits conferring an increased risk of adverse outcomes. We set out to determine how severity of frailty, as measured using the CFS, affected delirium rates, and recognition in hospitalised older people in the United Kingdom.
Methods:
Adults over 65 years were included in an observational multi-centre audit across UK hospitals, two prospective rounds, and one retrospective note review. Clinical Frailty Scale (CFS), delirium status, and 30-day outcomes were recorded.
Results:
The overall prevalence of delirium was 16.3% (483). Patients with delirium were more frail than patients without delirium (median CFS 6 vs 4). The risk of delirium was greater with increasing frailty [OR 2.9 (1.8–4.6) in CFS 4 vs 1–3; OR 12.4 (6.2–24.5) in CFS 8 vs 1–3]. Higher CFS was associated with reduced recognition of delirium (OR of 0.7 (0.3–1.9) in CFS 4 compared to 0.2 (0.1–0.7) in CFS 8). These risks were both independent of age and dementia.
Conclusion:
We have demonstrated an incremental increase in risk of delirium with increasing frailty. This has important clinical implications, suggesting that frailty may provide a more nuanced measure of vulnerability to delirium and poor outcomes. However, the most frail patients are least likely to have their delirium diagnosed and there is a significant lack of research into the underlying pathophysiology of both of these common geriatric syndromes
A matter of heart and life
https://place.asburyseminary.edu/atsconferences/2324/thumbnail.jp
The Methodist Conference in America: A History. By Russell E. Richey. Nashville, Tenn.: Kingswood Books, 1996. 304 pp. $17.95.
The Young John Wesley as Cross-Cultural Witness: Investigations into Wesley's American Mission Experience and Implications for Today's Mission
Discovery of Potent and Selective Benzothiazole Hydrazone Inhibitors of Bcl‑X<sub>L</sub>
Developing potent
molecules that inhibit Bcl-2 family mediated
apoptosis affords opportunities to treat cancers via reactivation
of the cell death machinery. We describe the hit-to-lead development
of selective Bcl-X<sub>L</sub> inhibitors originating from a high-throughput
screening campaign. Small structural changes to the hit compound increased
binding affinity more than 300-fold (to IC<sub>50</sub> < 20 nM).
This molecular series exhibits drug-like characteristics, low molecular
weights (<i>M</i><sub>w</sub> < 450), and unprecedented
selectivity for Bcl-X<sub>L</sub>. Surface plasmon resonance experiments
afford strong evidence of binding affinity within the hydrophobic
groove of Bcl-X<sub>L</sub>. Biological experiments using engineered
Mcl-1 deficient mouse embryonic fibroblasts (MEFs, reliant only on
Bcl-X<sub>L</sub> for survival) and Bax/Bak deficient MEFs (insensitive
to selective activation of Bcl-2-driven apoptosis) support a mechanism-based
induction of apoptosis. This manuscript describes the first series
of selective small-molecule inhibitors of Bcl-X<sub>L</sub> and provides
promising leads for the development of efficacious therapeutics against
solid tumors and chemoresistant cancer cell lines