Background The genetic determinants of the human innate immune response are poorly understood. Apolipoprotein (Apo) E, a lipid-trafficking protein that affects inflammation, has well-described ...wild-type (ε3) and disease-associated (ε2 and ε4) alleles, but its connection to human innate immunity is undefined. Objective We sought to define the relationship of APOε4 to the human innate immune response. Methods We evaluated APOε4 in several functional models of the human innate immune response, including intravenous LPS challenge in human subjects, and assessed APOε4 association to organ injury in patients with severe sepsis, a disease driven by dysregulated innate immunity. Results Whole blood from healthy APOε3 / APOε4 volunteers induced higher cytokine levels on ex vivo stimulation with Toll-like receptor (TLR) 2, TLR4, or TLR5 ligands than blood from APOε3 / APOε3 patients, whereas TLR7/8 responses were similar. This was associated with increased lipid rafts in APOε3/APOε4 monocytes. By contrast, APOε3 / APOε3 and APOε3 / APOε4 serum neutralized LPS equivalently and supported similar LPS responses in Apoe -deficient macrophages, arguing against a differential role for secretory APOE4 protein. After intravenous LPS, APOε3/APOε4 patients had higher hyperthermia and plasma TNF-α levels and earlier plasma IL-6 than APOε3/APOε3 patients. APOE4-targeted replacement mice displayed enhanced hypothermia, plasma cytokines, and hepatic injury and altered splenic lymphocyte apoptosis after systemic LPS compared with APOE3 counterparts. In a cohort of 828 patients with severe sepsis, APOε4 was associated with increased coagulation system failure among European American patients. Conclusions APOε4 is a determinant of the human innate immune response to multiple TLR ligands and associates with altered patterns of organ injury in human sepsis.
Medical Management at the Health Care Facility Gale, Stephen C., MD, FACS; Shiroff, Adam M., MD; Donovan, Colleen M., MD ...
Annals of emergency medicine,
01/2017, Letnik:
69, Številka:
1
Journal Article
Abstract Background After injury, base deficit (BD) and lactate are common measures of shock. Lactate directly measures anaerobic byproducts, whereas BD is calculated and multifactorial. Although ...recent studies suggest superiority for lactate in predicting mortality, most were small or analyzed populations with heterogeneous injury severity. Our objective was to compare initial BD with lactate as predictors of inhospital mortality in a large cohort of blunt trauma patients all presenting with hemorrhagic shock. Materials and methods The Glue Grant multicenter prospective cohort database was queried; demographic, injury, and physiologic parameters were compiled. Survivors, early deaths (≤24 h), and late deaths were compared. Profound shock (lactate ≥ 4 mmol/L) and severe traumatic brain injury subgroups were identified a priori . Chi-square, t -test, and analysis of variance were used as appropriate for analysis. Multivariable logistic regression and area under the receiver operating characteristic curve analysis assessed survival predictors. P < 0.05 was significant. Results A total of 1829 patients met inclusion; 289 (15.8%) died. Both BD and lactate were higher for nonsurvivors ( P < 0.00001). After multivariable regression, both lactate (odds ratio OR 1.17; 95% confidence interval CI: 1.12-1.23; P < 0.00001) and BD (OR 1.04; 95% CI: 1.01-1.07; P < 0.005) predicted overall mortality. However, when excluding early deaths ( n = 77), only lactate (OR 1.12 95% CI: 1.06-1.19; P < 0.0001) remained predictive but not BD (OR 1.00 95% CI: 0.97-1.04; P = 0.89). For the shock subgroup, ( n = 915), results were similar with lactate, but not BD, predicting both early and late deaths. Findings also appear independent of traumatic brain injury severity. Conclusions After severe blunt trauma, initial lactate better predicts inhospital mortality than initial BD. Initial BD does not predict mortality for patients who survive >24 h.
Evidence suggests that interruption of beta-blockers during acute decompensated heart failure (ADHF) in the absence of contraindications leads to poorer long-term outcomes. This study assesses ...whether similar effects occur when interrupting renin-angiotensin system inhibitor (RASi) therapy in ADHF. Data were retrospectively analyzed from patients admitted from 2015 to 2020 with ADHF and left ventricular ejection fraction (LVEF) ≤ 40% taking RASi therapy prior to admission. Patients were excluded if they required acute inotropic therapy or mechanical circulatory support, had worsening renal function (WRF), hyperkalemia, or symptomatic hypotension on admission. The primary endpoint was readmission for heart failure, which was analyzed using Cox regression analysis. One-hundred patients were included, with 22 patients in the interruption group and 78 patients in the continuation group. Baseline characteristics for each group were similar except for older age (67.4 vs 58.9 years;
= .014) and lower systolic blood pressure (120.5 vs 132.3 mm Hg;
= .037) in the interruption group. Interrupting RASi therapy was associated with a nonsignificant increase in the primary outcome (13.6% vs 5.1%;
= .177). Patients continuing RASi therapy were discharged on higher doses (10.1 vs 17.9 mg lisinopril equivalents;
= .044). Additionally, patients with interrupted RASi therapy were more likely to be re-admitted for WRF at 30-, 60-, and 90-day increments and at any-time after discharge (
< .05 for all). Adverse effects were similar except for more frequent hypotension in the interruption group at 72 hours (40.9% vs 14.1%;
= .013) and at any time (50% vs 19.2%;
= .004). In patients admitted for acute decompensated heart failure, RASi continuation in the absence of contraindications appears safe and was associated with more optimal guideline-directed medical therapy at discharge.
Optimal donor selection is critical for successful allogeneic hematopoietic cell transplantation (HCT). Donor sex and parity are well-established risk factors for graft-versus-host disease (GVHD), ...with male donors typically associated with lower rates of GVHD. Well-matched unrelated donors (URDs) have also been associated with increased risks of GVHD as compared with matched sibling donors. These observations raise the question of whether male URDs would lead to more (or less) favorable transplant outcomes as compared with parous female sibling donors. We used the Center for International Blood and Marrow Transplant Research registry to complete a retrospective cohort study in adults with acute myeloid leukemia, acute lymphoblastic leukemia, or myelodysplastic syndrome, who underwent T-cell replete HCT from these 2 donor types (parous female sibling or male URD) between 2000 and 2012. Primary outcomes included grade 2 to 4 acute GVHD (aGVHD), chronic GVHD (cGVHD), and overall survival. Secondary outcomes included disease-free survival, transplant-related mortality, and relapse. In 2813 recipients, patients receiving male URD transplants (n = 1921) had 1.6 times higher risk of grade 2 to 4 aGVHD (P < .0001). For cGVHD, recipient sex was a significant factor, so donor/recipient pairs were evaluated. Female recipients of male URD grafts had a higher risk of cGVHD than those receiving parous female sibling grafts (relative risk RR = 1.43, P < .0001), whereas male recipients had similar rates of cGVHD regardless of donor type (RR = 1.09, P = .23). Donor type did not significantly affect any other end point. We conclude that when available, parous female siblings are preferred over male URDs.
•Compared with parous female sibling donors, male URDs confer more aGVHD in all patients and more cGVHD in females.•There was no difference in survival, relapse, or transplant mortality between recipients of parous female sibling or male URD grafts.
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