Patients with hypothermic sepsis have a unique gene expression profile compared to patients with fever and sepsis

The pathophysiology of hypothermia during sepsis is unclear. Using genomic profiling of blood leukocytes, we aimed to determine if hypothermia is associated with a different gene expression profile compared to fever during sepsis. Patients with sepsis and either hypothermia or fever within 24 hours after ICU admission were included in the study (n = 168). Hypothermia was defined as body temperature below 36 °C. Fever was defined as body temperature equal to or above 38.3°C. We compared blood gene expression (whole-genome transcriptome in leukocytes) in hypothermic septic compared to febrile septic patients in an unmatched analysis and matched for APACHE IV score and the presence of shock. In total, 67 septic patients were hypothermic and 101 patients were febrile. Hypothermia was associated with a distinct gene expression profile in both unmatched and matched analyses. There were significant differences related to the up- and downregulation of canonical signalling pathways. In the matched analysis, the top upregulated gene was cold-inducible mRNA binding protein (CIRBP) which plays a role in cold-induced suppression of cell proliferation. In addition, we found three signalling pathways significantly upregulated in hypothermic patients compared to febrile patients; tryptophan degradation X, phenylalanine degradation IV and putrescine degradation III. In conclusion, there are distinct signalling pathways and genes associated with hypothermia, including tryptophan degradation and CIRBP expression, providing a possible link to the modulation of body temperature and early immunosuppression. Future studies may focus on the canonical signalling pathways presented in this paper to further investigate spontaneous hypothermia in sepsis

Induced normothermia ameliorates the procoagulant host response in human endotoxaemia

Background Dysregulation of coagulation occurs commonly in sepsis, ranging from mild coagulopathy with decreased platelets to disseminated intravascular coagulation (DIC). We investigated the effect of induced normothermia on coagulation during lipopolysaccharide (LPS)-induced endotoxaemia in healthy volunteers. Methods Twelve volunteers received an infusion of bacterial lipopolysaccharide (Escherichia coli; 2 ng kg−1) and were assigned to either induced normothermia or control. Induced normothermia to maintain core temperature at 37°C consisted of external surface cooling, cold i.v. fluids, and medication to reduce shivering (buspirone, clonidine, and magnesium sulphate). The primary outcome was the DIC score (International Society on Thrombosis and Haemostasis guideline). Prothrombin time (PT), activated partial thromboplastin time (aPTT), D-dimer, plasma von Willebrand factor (vWf), and rotational thromboelastometry (ROTEM) were measured before and 1, 3, 6, and 8 h after LPS infusion. Differences between groups were tested with a mixed effects model. Results In control subjects, lipopolysaccharide caused a fever, transiently decreased platelet levels and lowered activated partial thromboplastin time, while prolonging prothrombin time and increasing D-Dimer and vWf levels. Normothermia prevented the DIC-score exceeding 4, which occurred in 50% of control subjects. Normothermia also reduced the fall in platelet count by 67x109 L−1([95%CI:27-107]; p=0.002), aPTT (mean difference:3s [95%CI:1-5]; p=0.005) and lowered vWf levels by 89% ([95%CI:6-172]; p=0.03), compared to the fever group. ROTEM measurements were unaffected by lipopolysaccharide. Conclusion In human endotoxaemia, induced normothermia decreases markers of endothelial activation and DIC. Maintaining normothermia may reduce coagulopathy in hyperinflammatory states

Advancing Institutional Efforts to Support Research Mentorship: A Conceptual Framework and Self-Assessment Tool

Abstract The purpose of this article is to assist institutions in advancing their efforts to support research mentorship. The authors begin by describing how institutions can shape the key domains of research mentorship: (1) the criteria for selecting mentors, (2) incentives for motivating faculty to serve effectively as mentors, Acad Med. 2008; 83:217-225

Surgical outcomes of patients at prohibitive risk who are reconsidered for surgeryCentral MessagePerspective

Objectives: Transcatheter treatment of advanced mitral and tricuspid valve disease is largely limited to patients at prohibitive surgical risk, although many are not candidates for transcatheter treatment. Here, we describe surgical outcomes of patients at prohibitive risk who were ineligible for transcatheter therapies to guide surgeons in management of this unique population. Methods: Patients at prohibitive risk, defined per surgeon or cardiologist discretion, who were initially referred for a transcatheter mitral or tricuspid intervention in a multidisciplinary atrioventricular valve clinic, were identified from 2019 to 2022. Preoperative risk, operative outcomes, and long-term mortality were evaluated. Results: A total of 337 patients at prohibitive risk were referred for evaluation in a multidisciplinary atrioventricular valve clinic. Of those, 161 underwent transcatheter therapy, 130 patients underwent continued medical management, and 45 were reevaluated and had high-risk surgery. Among surgical patients, 51% were women with a median age of 76 years (quartile 1-quartile 3, 65-81 years). Most patients presented in heart failure (83%; n = 37 out of 45), and 73% were in New York Heart Association functional class III or IV. Most patients (94%; n = 43) had a mitral valve intervention, of whom 56% (24 out of 43) had a mitral valve replacement. The 30-day mortality rate was 4% (2 out of 45) and major morbidity occurred in 33% (15 out of 45). By Kaplan-Meier analysis, 1-year survival was 86% ± 9%. Conclusions: Select patients at prohibitive risk who were ineligible for transcatheter mitral or tricuspid valve intervention underwent surgery with overall low operative mortality and excellent 1-year survival. Patients a prohibitive risk whose anatomy is not amenable to transcatheter devices should be reconsidered for surgery