Influence of blood storage age on immune and coagulation parameters in critically ill transfused patients.

BACKGROUND: Several retrospective studies have suggested that transfusion with red blood cells (RBCs) stored for longer periods is associated with increased mortality. The Age of Blood Evaluation (ABLE) study randomized subjects to receive fresh vs. standard issue RBC units and showed no difference in the primary or secondary endpoints of mortality or change in multi-organ dysfunction syndrome (MODS) score. METHODS: In this study a subset of 100 ABLE subjects were enrolled to measure coagulation and immune parameters. Samples were collected pre-transfusion and on days 2, 6, 28, and 180 post-transfusion. Levels of 16 coagulation parameters, regulatory and functional T cells, 25 cytokines, and 16 markers of extracellular vesicles (EVs) were determined. RESULTS: Changes from baseline in levels of protein C, factor V, and EVs expressing phosphatidyl serine and CTLA-4 (CD152) differed between recipients of fresh and standard storage age RBC units, with the vast majority of coagulation and EV markers and all cytokines tested showing no difference between study arms. Although most analytes showed no difference between subjects in the fresh and standard arms of the study, 6 coagulation parameters, 15 cytokines, and 7 EV parameters changed significantly in the period post-transfusion. DISCUSSION: Transfusion of fresh vs. standard issue RBC units does not result in substantial changes in coagulation or immune parameters, up to day 35 of RBC storage. Furthermore, significant changes in multiple coagulation and immune parameters are detectable post-transfusion, though causality cannot be determined based on the current study.

Granulocyte-Derived Extracellular Vesicles Activate Monocytes and Are Associated With Mortality in Intensive Care Unit Patients.

To understand how extracellular vesicle (EV) subtypes differentially activate monocytes, a series of in vitro studies were performed. We found that plasma-EVs biased monocytes toward an M1 profile. Culturing monocytes with granulocyte-, monocyte-, and endothelial-EVs induced several pro-inflammatory cytokines. By contrast, platelet-EVs induced TGF-ß and GM-CSF, and red blood cell (RBC)-EVs did not activate monocytes in vitro. The scavenger receptor CD36 was important for binding of RBC-EVs to monocytes, while blockade of CD36, CD163, CD206, TLR1, TLR2, and TLR4 did not affect binding of plasma-EVs to monocytes in vitro. To identify mortality risk factors, multiple soluble factors and EV subtypes were measured in patients' plasma at intensive care unit admission. Of 43 coagulation factors and cytokines measured, two were significantly associated with mortality, tissue plasminogen activator and cystatin C. Of 14 cellular markers quantified on EVs, 4 were early predictors of mortality, including the granulocyte marker CD66b. In conclusion, granulocyte-EVs have potent pro-inflammatory effects on monocytes in vitro. Furthermore, correlation of early granulocyte-EV levels with mortality in critically ill patients provides a potential target for intervention in management of the pro-inflammatory cascade associated with critical illness.

Obstetric fistula in Niger: 6-month postoperative follow-up of 384 patients from the Danja Fistula Center.

INTRODUCTION AND HYPOTHESIS: The impoverished West African country of Niger has high rates of obstetric fistula. We report a 6-month postoperative follow-up of 384 patients from the Danja Fistula Center and assess factors associated with operative success or failure. METHODS: The medical records of 384 women who had completed a 6-month follow-up after fistula surgery were reviewed. Cases were categorized as "easy," "of intermediate complexity," or "difficult" based on a preoperative points system. Data were analyzed using simple chi-squared statistics and logistic regression. RESULTS: The patients were predominantly of Hausa ethnicity (73%), married young (average 15.9 years), had teenage first pregnancies (average first delivery 16.9 years), and experienced prolonged labor (average 2.3 days) with poor outcomes (89% stillbirth rate). The average parity was four. Patients commonly developed their fistula during their first delivery (43.5%), but over half sustained a fistula during a subsequent delivery (56.5%). Prior fistula surgery elsewhere (average 1.75 operations) was common. The overall surgical success ("closed and dry") was 54%. When the 134 primary operations were analyzed separately, the overall success rate was 80%. Increasing success was seen with decreasing surgical difficulty: 92% success for "easy" cases, 68% for "intermediate" cases, and 57% success for "difficult" cases. Success decreased with increasing numbers of previous attempts at surgical repair. CONCLUSIONS: These data provide further evidence that clinical outcomes are better when primary fistula repair is performed by expert surgeons in specialist centers with the support of trained fistula nurses.

Epistatic interactions of CDKN2B-TCF7L2 for risk of type 2 diabetes and of CDKN2B-JAZF1 for triglyceride/high-density lipoprotein ratio longitudinal change: evidence from the Framingham Heart Study.

UNLABELLED: Fifteen known type 2 diabetes (T2D) gene variants were assessed for their associations with T2D status in 228 T2D families from the Framingham Heart Study (FHS) Original, Offspring, and Children Cohorts. Bayesian approach was used to test single-single-nucleotide polymorphism (SNP) association followed by logistic regression. Bayesian and logic regression approaches were used to test multiple SNP association searching for the best combinations of variants followed by logistic regression reconfirmation. The significant variants for T2D risk were also tested for their main and interacting effects on triglyceride (TG)/high-density lipoprotein (HDL) ratio change derived from four point measures across time. This slope phenotype was made available using mixed model growth curve approach from 155 T2D families in the FHS Offspring Cohort. RESULTS: CDKN2B rs10811661 (p = 0.042), TCF7L2 rs4506565 (p = 0.004), and JAZF1 rs864745 (p = 0.04) were individually associated with risk of T2D (OR = 1.0-2.0; effect size <1%). CDKN2B and TCF7L2 were found with significant main (p = 0.02, 0.01) and interacting (p = 0.05) effects for increased (OR = 3.0) risk of T2D. CDKN2B and JAZF1 were found with significant main (p = 0.0002 and 0.034) and interacting (p = 0.001) effects on increased (beta = 0.42) TG/HDL ratio longitudinal change. These interacting effects were independent of effects of age and sex with effect sizes of 0.3-0.4% for risk of T2D or TG/HDL ratio longitudinal change. CONCLUSION: These synthetic approaches allowed for successful detection of CDKN2B and TCF7L2 interacting effect for T2D risk and CDKN2B and JAZF1 interacting effect on TG/HDL ratio increase over time among T2D families in the FHS. These interacting effects were consistent in conferring risk of T2D or progressive insulin resistance with modest effect sizes.

Longitudinal and age trends of metabolic syndrome and its risk factors: the Family Heart Study.

BACKGROUND: We report longitudinal changes in the metabolic syndrome (MetS) in 2,458 participants from 480 families in the Family Heart Study. Participants were examined between 1994-96 (FHS-T1) and 2002-03 (FHS-T2), about 7.4 years apart. Additionally, the impact of medication on estimates of MetS prevalence, and associations of MetS with prevalent coronary heart disease (CHD) and type 2 diabetes (T2D) were studied. METHODS: Three definitions for MetS prevalence were considered. One represented the original (o) National Cholesterol Education Program (NCEP) MetS criteria. Two others considered the confounding of medications effects, respectively (m) lipid medications constituted a categorical diagnostic criterion for lipids variables, and (c) lipids and blood pressure variables were corrected with average clinical trials medications effects. Logistic regression of MetS on CHD and T2D, as well as the trend analysis of MetS by age, were performed. RESULTS: MetS increased from 17.1% in FHS-T1(o) to 28.8% in FHS-T2(o); from 19.7% in FHS-T1(m) to 42.5% in FHS-T2(m); and from 18.4% in FHS-T1(c) to 33.6% in FHS-T2(c). While we observed adverse changes in all risk factors, the greatest increase was for waist circumference (25%). The percentages of MetS were about 2 to almost 3 times higher in ages 50 years and older than in younger ages. The odds of having prevalent CHD were about 2.5 times higher in the subjects classified with MetS than without. CONCLUSION: MetS percentages increased noticeably longitudinally and cross-sectionally with older age. These conclusions were reached with and without considering medication use, but correcting risk factors for medications use affects the MetS prevalence estimates. As found in other studies, MetS was associated with increased odds for prevalent CHD.

Hostility and physiological risk in the National Heart, Lung, and Blood Institute Family Heart Study.

BACKGROUND: The present analyses investigated possible pathways for earlier reported associations in the National Heart, Lung, and Blood Institute Family Heart Study between hostility and coronary and carotid end points. METHODS: The cross-sectional design recruited 535 women and 491 men with average familial risk for coronary heart disease and 1950 women and 1667 men with high familial coronary risk from 3 prospective ongoing studies at 4 sites. Recruitment of high-risk participants was based on family risk score. Average-risk participants came from a randomly selected group. Outcome measures were plasminogen activator inhibitor type 1 (PAI-1), homocysteine, fibrinogen, fasting glucose, blood pressure, high-density lipoprotein cholesterol, triglycerides, low-density lipoprotein cholesterol, and "lipid metabolic disorder" (LMD) (defined as systolic blood pressure >/=140 mm Hg or diastolic blood pressure >/=90 mm Hg); fasting glucose >/=126 mg/dL (>/=7.0 mmol/L) or the use of diabetes medications; body mass index (calculated as weight in kilograms divided by the square of height in meters) >/=30; triglycerides >/=250 mg/dL (>/=2.8 mmol/L), high-density lipoprotein cholesterol <40 mg/dL (<1.0 mmol/L) in men and <50 mg/dL (<1.3 mmol/L) in women; and low-density lipoprotein cholesterol level >/=130 mg/dL (>/=3.4 mmol/L). RESULTS: After adjustment for age and risk-related behaviors, hostility was significantly associated with glucose level and LMD in high-risk women, with LMD in average-risk women, with PAI-1 and LMD in high-risk men, and with fibrinogen level in average-risk men. CONCLUSIONS: Associations between hostility and physiological risk were only partially accounted for by health behaviors, suggesting that further investigation of mechanistic pathways is warranted.