An evaluation of risk factors to predict target concentration non-attainment in critically ill patients prior to empiric β-lactam therapy

To determine whether target concentration non-attainment can be anticipated in critically ill patients prior to initiating empiric β-lactam antibiotic therapy based on readily available clinical factors. Retrospective review of consecutive patients treated with piperacillin or meropenem and who underwent therapeutic drug monitoring (TDM) at St Vincent’s Hospital (Sydney, Australia) between January 2013 and December 2015 was performed. Predefined subgroups were patients who received continuous renal replacement therapy (CRRT) and those who did not (non-CRRT). Potential risk factors were evaluated by correlation with β-lactam antibiotic trough concentrations (C_min) lower than or equal to targeted minimum inhibitory concentration (MIC). Only the first drug concentration after initiation of the antibiotic treatment was included to reflect empirical dose selection. A total of n?=?249 patients (piperacillin, n?=?169; meropenem, n?=?80) were investigated. For non-CRRT patients (n?=?210), multivariate analysis demonstrated the following: male gender (p?=?0.006); younger age (p?=?0.015); prescribed daily antibiotic dose less than 1.5 times the product information recommendations (p?=?0.004); lack of positive microbiology (p?=?0.006); lower overall illness severity (p?=?0.005); and estimated glomerular filtration rate (eGFR) ≥?90 mL/min/1.73 m² (p?<?0.001), to be associated with C_min?≤?MIC. No predictor variable was found to be significantly associated with C_min?≤?MIC for the CRRT cohort. Evaluating the risk of target concentration non-attainment using simple clinical factors is possible at the bedside for non-CRRT patients prior to empiric antibiotic initiation. Clinicians should be wary of selecting doses based on the product information especially when treating younger male patients with apparently ‘normal’ renal function.     

Serum apolipoprotein B predicts dyslipidemia, metabolic syndrome and, in women, hypertension and diabetes, independent of markers of central obesity and inflammation

OBJECTIVES: To investigate the role of serum apolipoprotein (apo) B levels in predicting metabolic syndrome (MS), hypertension, atherogenic dyslipidemia and type II diabetes. METHODS: Prospective evaluation of 1125 men and 1223 women, aged 28-74 years, participating in the survey 1997/1998 who had serum apo B determinations and were followed-up for a mean 5.9 years. Tertiles of apo B were formed by cut points by 120 and 95 mg/dl. MS was defined by modified ATPIII criteria. RESULTS: Apo B values exhibited no significant difference among sexes. Low-density lipoprotein (LDL)-cholesterol and triglycerides were their leading determinants on linear regression analysis. By logistic regression analyses, the top versus bottom apo B tertile predicted significantly newly developing MS in both sexes separately with two-fold relative risks (RRs) (P<0.02) and the development of high triglyceride/low high-density lipoprotein-cholesterol dyslipidemia with nearly threefold RRs (P=0.001), after adjustment for waist circumference, C-reactive protein (CRP), physical activity grade and family income category. Development of hypertension was predicted only in women by the apo B top tertile (fully adjusted RR 1.71 [95% CI 1.001; 2.92]), while the significance of the prediction regarding age-adjusted diabetes in women (RR 1.86 [95% CI 1.04; 3.36]) attenuated after adjustment for the stated confounding factors. CONCLUSIONS: Apo B concentrations, which reflect the number of small, dense LDL particles in plasma, are a significant predictor of cardiometabolic risk among adults with a high prevalence of MS, independent of waist circumference and CRP.     

Cross-sectional study of complement C3 as a coronary risk factor among men and women

In the present study, we examined (i) whether C3 (complement C3) was an independent marker of prevalent CHD (coronary heart disease), and (ii) which preferential associations existed between C3 and some cardiovascular risk factors when jointly analysed with CRP (C-reactive protein) and fibrinogen. In a cohort of 756 unselected adults, 39% of whom had the metabolic syndrome, C3 and other risk variables were evaluated in a cross-sectional manner. In a logistic regression model for the likelihood of CHD, a significant OR (odds ratio) of 3.5 [95% CI (confidence intervals), 1.27 and 9.62)] for C3 was obtained after adjustment for smoking status, TC (total cholesterol) and usage of statins. A similar model, also comprising systolic blood pressure, with a cut-off point of >or=1.6 g/l C3 exhibited a 1.9-fold risk (95% CI, 1.01 and 3.58) compared with individuals below the cut-off point. Both analyses displayed an adjusted OR of 1.37 for each S.D. increment in C3. The significant relationship of C3 with a likelihood of CHD also proved to be independent of CRP. In multiple linear regression models, associations were tested for each acute-phase protein with measures of obesity, fasting insulin, triacylglycerols (triglycerides), TC, HDL (high-density lipoprotein)-cholesterol, physical activity, smoking status, diagnosis of metabolic syndrome and family income. When both genders were combined, C3 was independently associated with serum triacylglycerols, waist circumference, BMI (body mass index) and TC. CRP was independently associated with waist circumference, TC, family income (inversely) and physical activity, and fibrinogen with BMI, TC, smoking status and metabolic syndrome. In summary, elevated levels of complement C3 are associated with an increased likelihood of CHD independent of standard risk factors and regardless of the presence of acute coronary events, suggesting that C3 might be actively involved in coronary atherothrombosis. Unlike CRP and fibrinogen, C3 was preferentially associated with waist girth and serum triacylglycerols.     

Development and activation of regulatory T cells in the human fetus

There is an increasing amount of knowledge on the functional properties of regulatory T cells (Treg) in the adult immune system, but data on the generation and function of these cells during human embryonic development are scarce. In this study, we show that in the fetal thymus, double-positive cells initiate expression of CD25, GITR, CTLA4 and CD122 during their transition from the CD27- to the CD27+ stage. Moreover, CD4+CD25+ fetal thymocytes already have the potential to suppress proliferation of CD25- cells. After leaving the thymus, FoxP3+CD4+CD25+ Treg enter the fetal lymph nodes and spleen, where they acquire a primed/memory phenotype. A model is proposed for the development of human fetal Treg that encompasses two sequential maturation steps: initiation of a regulatory phenotype and suppressive activity in the thymus; and subsequent activation within the peripheral lymphoid organs. Upon activation, FoxP3+CD4+CD25+ Treg suppress potentially deleterious responses by autoreactive lymphocytes and maintain homeostasis within the developing fetus.     

CD70 represents the human ligand for CD27

The recently identified CD27 ligand (L) Is a type II transmembranemolecule with significant structural homology to tumor necrosisfactor (TNF)-, TNF-ß, lymphotoxin ß, CO40L,and CD30L. Using a CD27L specific mAb we examined the tissuedistribution of the molecule, and found Its expression to berestricted to B cells in occasional germinal centers, stromalcells in the thymic medulla, and scattered T cells in tonsils,skin and gut. As the limited expression of CD27L closely resembledthe reported distribution of the activation antigen CD70, wetested whether CD70 represents the human CD27L. CD70 mAb werefound to react with CD27L-expressing transfected mouse fibroblasts.Moreover a number of CD70 mAb could specifically interfere withthe cellular binding of CD27L mAb. Thus, CD70 Is Identical tothe human CD27L.