Cholesterol, Amyloid Beta, Fructose, and LPS Influence ROS and ATP Concentrations and the Phagocytic Capacity of HMC3 Human Microglia Cell Line.

Research has found that genes specific to microglia are among the strongest risk factors for Alzheimer's disease (AD) and that microglia are critically involved in the etiology of AD. Thus, microglia are an important therapeutic target for novel approaches to the treatment of AD. High-throughput in vitro models to screen molecules for their effectiveness in reversing the pathogenic, pro-inflammatory microglia phenotype are needed. In this study, we used a multi-stimulant approach to test the usefulness of the human microglia cell 3 (HMC3) cell line, immortalized from a human fetal brain-derived primary microglia culture, in duplicating critical aspects of the dysfunctional microglia phenotype. HMC3 microglia were treated with cholesterol (Chol), amyloid beta oligomers (AßO), lipopolysaccharide (LPS), and fructose individually and in combination. HMC3 microglia demonstrated changes in morphology consistent with activation when treated with the combination of Chol + AßO + fructose + LPS. Multiple treatments increased the cellular content of Chol and cholesteryl esters (CE), but only the combination treatment of Chol + AßO + fructose + LPS increased mitochondrial Chol content. Microglia treated with combinations containing Chol + AßO had lower apolipoprotein E (ApoE) secretion, with the combination of Chol + AßO + fructose + LPS having the strongest effect. Combination treatment with Chol + AßO + fructose + LPS also induced APOE and TNF-α expression, reduced ATP production, increased reactive oxygen species (ROS) concentration, and reduced phagocytosis events. These findings suggest that HMC3 microglia treated with the combination of Chol + AßO + fructose + LPS may be a useful high-throughput screening model amenable to testing on 96-well plates to test potential therapeutics to improve microglial function in the context of AD.

Transcriptomic and glycomic analyses highlight pathway-specific glycosylation alterations unique to Alzheimer's disease.

Glycosylation has been found to be altered in the brains of individuals with Alzheimer's disease (AD). However, it is unknown which specific glycosylation-related pathways are altered in AD dementia. Using publicly available RNA-seq datasets covering seven brain regions and including 1724 samples, we identified glycosylation-related genes ubiquitously changed in individuals with AD. Several differentially expressed glycosyltransferases found by RNA-seq were confirmed by qPCR in a different set of human medial temporal cortex (MTC) samples (n = 20 AD vs. 20 controls). N-glycan-related changes predicted by expression changes in these glycosyltransferases were confirmed by mass spectrometry (MS)-based N-glycan analysis in the MTC (n = 9 AD vs. 6 controls). About 80% of glycosylation-related genes were differentially expressed in at least one brain region of AD participants (adjusted p-values < 0.05). Upregulation of MGAT1 and B4GALT1 involved in complex N-linked glycan formation and galactosylation, respectively, were reflected by increased concentrations of corresponding N-glycans. Isozyme-specific changes were observed in expression of the polypeptide N-acetylgalactosaminyltransferase (GALNT) family and the alpha-N-acetylgalactosaminide alpha-2,6-sialyltransferase (ST6GALNAC) family of enzymes. Several glycolipid-specific genes (UGT8, PIGM) were upregulated. The critical transcription factors regulating the expression of N-glycosylation and elongation genes were predicted and found to include STAT1 and HSF5. The miRNA predicted to be involved in regulating N-glycosylation and elongation glycosyltransferases were has-miR-1-3p and has-miR-16-5p, respectively. Our findings provide an overview of glycosylation pathways affected by AD and potential regulators of glycosyltransferase expression that deserve further validation and suggest that glycosylation changes occurring in the brains of AD dementia individuals are highly pathway-specific and unique to AD.

Effects of Season, Location, Species, and Sex on Hematologic and Plasma Biochemical Values and Body Mass in Free-ranging Grebes (Aechmophorus species).

The effects of season, location, species, and sex on body weight and a comprehensive array of blood chemistry and hematology analytes were compared for free-ranging western (Aechmophorus occidentalis) and Clark's (Aechmophorus clarkii) grebes. Birds (n = 56) were collected from Puget Sound, WA, and Monterey Bay and San Francisco Bay, CA, from February 2007 to March 2011. The data supported generalization of observed ranges for most analytes across Aechmophorus grebe metapopulations wintering on the Pacific coast. Notable seasonal and location effects were observed for packed cell volume (winter 6% greater than fall; winter California [CA] 5% greater than Washington [WA]), total white blood cell count (CA 3.57 × 103 cells/µL greater than WA), heterophils (WA 10% greater than CA), lymphocytes (winter 19% greater than fall), heterophil to lymphocyte ratio (fall 5.7 greater than winter), basophils (CA greater than WA), plasma protein (WA about 10 g/L [1.0 g/dL] greater than CA), plasma protein to fibrinogen ratio (winter about 15 greater than fall), potassium (CA 2 mmol/L greater than WA), and liver enzymes (alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase: WA greater than CA). Within California, season had a greater effect on body mass than sex (mean winter weights about 200 g greater than fall), whereas within a season, males weighed only about 80 g more than females, on average. These data give biologists and veterinarians quantitative reference values to better assess health at the individual and metapopulation level.

AN EXPERIMENTAL STUDY OF THE EFFECTS OF CHEMICALLY DISPERSED OIL ON FEATHER STRUCTURE AND WATERPROOFING IN COMMON MURRES ( URIA AALGE).

Following an oil spill in the marine environment, chemical dispersants, which increase oil droplet formation and distribution into the water column, are assumed to provide a net benefit to seabirds by reducing the risk of exposure to oil on the water surface. However, few data are available regarding acute, external impacts of exposure to dispersed oil. We evaluated the effects of known concentrations of dispersant and crude oil in artificial seawater on live Common Murres ( Uria aalge). Waterproofing and microscopic feather geometry were evaluated over time and compared to pre-exposure values. Birds exposed to a high concentration of dispersant experienced an immediate, life-threatening loss of waterproofing and buoyancy, both of which resolved within 2 d. Birds exposed to oil, or a dispersant and oil mixture, experienced dose-dependent waterproofing impairment without resolution over 2 d. Alterations in feather geometry were observed in oil-exposed or dispersant- and oil-exposed birds and were associated with increased odds of waterproofing impairment compared to control birds. At a given contaminant concentration, there were no significant differences in waterproofing between oil-exposed and dispersant- and oil-exposed birds. We found that acute, external effects of oil and dispersed oil exposure are comparable and dose-dependent. Our results also indicate that a zero-risk assumption should not be used when seabirds are present within the dispersant application zone.

Mediating Effect of Postsurgical Chemotherapy on Presence of Dementia and Survival among Patients 65 and Older with Stage III Colon Cancer.

Introduction: Both colon cancer and dementia are prevalent among the elderly and have a high risk of cooccurrence. Previous studies found that patients with dementia were treated less aggressively. In this study, we hypothesized that presence of preexisting dementia was associated with worse survival for stage III colon cancer patients, and that postoperative chemotherapy was on the causal pathway.Methods: We defined preexisting dementia in Surveillance Epidemiology and End Results Medicare data through either a formal diagnosis or a prescription for dementia drugs or both before the diagnosis of cancer. We applied multivariable Cox regression to estimate the effect of preexisting dementia on survival, adjusting for demographic factors, tumor characteristics, and receipt of chemotherapy. We assessed mediating effects in the context of the counterfactual framework using the accelerated failure time model.Results: There were 4,573 patients diagnosed with stage III colon cancer between 2007 and 2009 identified. A preexisting diagnosis of dementia significantly increased the risk of death by 45% (HR = 1.45, 95% CI: 1.29-1.63). Patients with either a formal diagnosis of dementia or a related prescription had significantly lower cause-specific survival than their cognitively healthy counterparts. Receipt of chemotherapy was a significant mediator on the causal pathway. The effect of presence of dementia was mediated by receipt of chemotherapy by 13% for preexisting dementia.Conclusions: Preexisting dementia is significantly associated with worse survival for stage III colon cancer patients, and its deleterious effect is partially explained by decreased likelihood of postoperative chemotherapy receipt.Impact: This is the first study that provides estimate of the mediating effect of diminished chemotherapy in patients with stage III colon cancer and dementia, simultaneously demonstrating the cancer-specific survival benefit of chemotherapy in the presence of dementia. Cancer Epidemiol Biomarkers Prev; 26(10); 1558-63. ©2017 AACR.

The Human Serum Metabolome of Vitamin B-12 Deficiency and Repletion, and Associations with Neurological Function in Elderly Adults.

BACKGROUND: The specific metabolomic perturbations that occur in vitamin B-12 deficiency, and their associations with neurological function, are not well characterized. OBJECTIVE: We sought to characterize the human serum metabolome in subclinical vitamin B-12 deficiency and repletion. METHODS: A before-and-after treatment study provided 1 injection of 10 mg vitamin B-12 (with 100 mg pyridoxine and 100 mg thiamin) to 27 community-dwelling elderly Chileans (∼74 y old) with vitamin B-12 deficiency, as evaluated with serum vitamin B-12, total plasma homocysteine (tHcy), methylmalonic acid (MMA), and holotranscobalamin. The combined indicator of vitamin B-12 status (cB-12) was computed. Targeted metabolites [166 acylcarnitines, amino acids, sugars, glycerophospholipids, and sphingolipids (liquid chromatography-tandem mass spectrometry)], and untargeted metabolites [247 chemical entities (gas chromatography time-of-flight mass spectrometry)] were measured at baseline and 4 mo after treatment. A peripheral nerve score was developed. Differences before and after treatment were examined. For targeted metabolomics, the data from 18 individuals with adequate vitamin B-12 status (selected from the same population) were added to the before-and-after treatment data set. Network visualizations and metabolic pathways are illustrated. RESULTS: The injection increased serum vitamin B-12, holotranscobalamin, and cB-12 (P < 0.001), and reduced tHcy and serum MMA (P < 0.001). Metabolomic changes from before to after treatment included increases (P < 0.001) in acylcarnitines, plasmalogens, and other phospholipids, whereas proline and other intermediaries of one-carbon metabolism-that is, methionine and cysteine-were reduced (P < 0.001). Direct significant correlations (P < 0.05 after the false discovery rate procedure) were identified between acylcarnitines, plasmalogens, phospholipids, lyso-phospholipids, and sphingomyelins compared with vitamin B-12 status and nerve function. Multiple connections were identified with primary metabolites (e.g., an inverse relation between vitamin B-12 markers and tryptophan, tyrosine, and pyruvic, succinic, and citric acids, and a direct correlation between the nerve score and arginine). CONCLUSIONS: The human serum metabolome in vitamin B-12 deficiency and the changes that occur after supplementation are characterized. Metabolomics revealed connections between vitamin B-12 status and serum metabolic markers of mitochondrial function, myelin integrity, oxidative stress, and peripheral nerve function, including some previously implicated in Alzheimer and Parkinson diseases. This trial was registered at www.controlled-trials.com as ISRCTN02694183.

Surrogate End Points for Overall Survival in Metastatic, Locally Advanced, or Unresectable Pancreatic Cancer: A Systematic Review and Meta-Analysis of 24 Randomized Controlled Trials.

BACKGROUND: Overall survival (OS) has traditionally been the primary end point in studies evaluating the clinical benefit of first-line chemotherapy in metastatic, locally advanced, or unresectable pancreatic cancer (MLAUPC). Given the prolonged follow-up assessment required to obtain OS and its potential to be confounded by second-line treatments, this study sought to determine whether progression-free survival (PFS), response rate (RR), or disease control rate (DCR) can serve as a reliable surrogate for OS. METHODS: A systematic review and meta-analysis was performed including all phase 3 clinical trials for MLAUPC, with gemcitabine as the control arm of the trial. The hazard ratios (HRs) for OS and PFS and odds ratios (ORs) for RR and DCR were recorded. A weighted Pearson correlation coefficient was estimated for the association between OS and the other outcomes. The primary analysis used a random effects weighting model, whereas the secondary analyses used a fixed effects- or sample size-weighted approach. RESULTS: For the study, 24 randomized controlled trials were identified. The Pearson correlation coefficient between OS and PFS was 0.86 (95% confidence interval [CI] 0.67-0.94; p < 0.001). Sensitivity analysis of the studies with little to no crossover further showed a correlation coefficient of 0.91 (95% CI 0.76-0.97; p < 0.001). The correlation coefficient between OS and RR was 0.45 (95% CI 0.07-0.72; p = 0.02) and between OS and DCR was 0.74 (95% CI 0.38-0.90; p < 0.001). CONCLUSIONS: First-line chemotherapy trials for MLAUPC show a robust correlation between OS and PFS, affirming its role as a surrogate of OS.

ß-amyloid, hippocampal atrophy and their relation to longitudinal brain change in cognitively normal individuals.

Recent literature has examined baseline hippocampal volume and extent of brain amyloidosis to test potential synergistic effects on worsening cognition and extent of brain atrophy. Use of hippocampal volume in prior studies was based on the notion that limbic circuit degeneration is an early manifestation of the Alzheimer's Disease (AD) pathophysiology. To clarify these interactions early in the AD process, we tested the effects of amyloid and baseline normalized hippocampal volume on longitudinal brain atrophy rates in a group of cognitively normal individuals. Results showed that the combination of elevated ß-amyloid and baseline hippocampal atrophy is associated with increased rates specific to the limbic circuit and splenium. Importantly, this atrophy pattern emerged from a voxelwise analysis, corroborated by regression models over region of interests in native space. The results are broadly consistent with previous studies of the effects of amyloid and baseline hippocampal atrophy in normals, while pointing to accelerated atrophy of AD-vulnerable regions detectable at the preclinical stage.

A multivariate cure model for left-censored and right-censored data with application to colorectal cancer screening patterns.

We develop a multivariate cure survival model to estimate lifetime patterns of colorectal cancer screening. Screening data cover long periods of time, with sparse observations for each person. Some events may occur before the study begins or after the study ends, so the data are both left-censored and right-censored, and some individuals are never screened (the 'cured' population). We propose a multivariate parametric cure model that can be used with left-censored and right-censored data. Our model allows for the estimation of the time to screening as well as the average number of times individuals will be screened. We calculate likelihood functions based on the observations for each subject using a distribution that accounts for within-subject correlation and estimate parameters using Markov chain Monte Carlo methods. We apply our methods to the estimation of lifetime colorectal cancer screening behavior in the SEER-Medicare data set. Copyright © 2016 John Wiley & Sons, Ltd.

The risk and burden of smoking related heart disease mortality among young people in the United States.

PURPOSE: Although cigarette smoking remains the most common risk factor for heart disease among the young, few studies have explored the relationship of smoking with heart disease mortality risk among young people. This prospective study assesses the risk and burden of all heart disease (HD) and coronary heart disease (CHD) mortality associated with smoking among younger adults from a nationally representative sample of the United States. METHOD: National Health Interview Survey respondents' data from 1997-2004 were linked to their death records through 2006. The analyses were restricted to individuals 18 to 44 years of age during follow up (n = 121,284). Cox proportional hazard ratios (HR) were estimated with adjustment for sample weights and design effects. Attributable fractions (AF) of smoking were calculated. RESULTS: After controlling for age, race, body mass index, history of hypertension and diabetes, and leisure time physical activity, current smoking related CHD mortality HR was 14.6 [95 % confidence interval or CI, 3.3-64.9] for females and 3.6 [95 % CI, 1.2-10.4] for males. The HR for all HD mortality was 3.1 [95 % CI, 1.3-7.6] for females and 2.4 [95 % CI, 1.2-4.7] for males. The AF of smoking for CHD deaths for female and male were 0.58 and 0.54 respectively. The AF of all HD mortality was 0.31 for male and 0.32 for female. The mean estimates of all HD deaths attributable to smoking during 1997-2006 among this age group were 52,214, of which 45,147 were CHD deaths. CONCLUSION: Even after adjustment for multiple risk factors and without addressing passive smoking, our result showed a strong relationship between smoking and HD and CHD mortality among young adults that is likely causal.

Association between high-sensitivity C-reactive protein (hsCRP) and change in mammographic density over time in the SWAN mammographic density subcohort.

PURPOSE: High mammographic density (MD) is a strong risk factor for breast cancer. Chronic inflammation may be related to breast cancer risk through a mechanism involving the percent of breast area that is dense (percent MD). Longitudinal assessments, however, are lacking and thus were constructed to evaluate the relationship between chronic inflammation and percent MD. METHODS: We evaluated whether elevated (>3 mg/L) high-sensitivity C-reactive protein (hsCRP), a biomarker of inflammation, was associated with change in percent MD among 653 women aged 42-52 years at baseline in the Study of Women's Health Across the Nation, a longitudinal study of midlife women. We used a mixed model to analyze data from an average of 4.7 mammograms per woman collected during an average follow-up of 4.9 years (SD = 1.47). RESULTS: Elevated hsCRP at baseline was associated with lower baseline percent MD and a significantly slower annual decline over time of percent MD in an adjusted model that did not include body mass index (BMI) (ß = 0.88, 95 % CI 0.44, 1.31). This association was attenuated and nonsignificant when BMI was included in the model (ß = 0.37, 95 % CI -0.09, 0.84). Elevated hsCRP levels over time (time-varying elevated hsCRP levels) were also associated with a significantly slower decline in percent MD (ß = 0.62, 95 % CI 0.30, 0.94). This association was attenuated, but still significant after adjusting for baseline BMI (ß = 0.40, 95 % CI 0.07, 0.73). CONCLUSION: These results suggest that inflammation may be related to slower reduction in percent MD.

Reticulocyte hemoglobin content testing for iron deficiency in healthy toddlers.

OBJECTIVES: To investigate reticulocyte hemglobin content (CHr) as a primary screening test to detect iron deficiency (ID) in healthy toddlers. Demographic and dietary risk factors associated with ID were studied for an association with low CHr. METHODS: This was a prospective cross-sectional study of healthy toddlers aged 12 to 36 months coming to well-child visits at two military pediatric ambulatory clinics in the Washington, DC, area from August 2006 to November 2007. Data were collected on medical, demographic, and dietary intake by parental questionnaire. A sample of blood was drawn from each subject for complete blood count and CHr. A logistic regression model was used to determine which factors may be predictive of ID. RESULTS: A total of 144 children were studied. An abnormal low CHr of 27.5 was identified in 18.8% of our toddler population. Two variables were determined to be independent predictors of low CHr; an age of 12 to 23 months and black race. CONCLUSIONS: Used alone as a primary screening marker, CHr identified a high prevalence of ID in our population of toddlers. Black race and younger age were associated with a lower CHr. Larger studies are needed to confirm these findings.

Metabolic syndrome and mammographic density: the Study of Women's Health Across the Nation.

The metabolic syndrome (MetS) is associated with an increase in breast cancer risk. In our study, we evaluated whether the MetS was associated with an increase in percent mammographic density (MD), a breast cancer risk factor. We used linear regression and mixed models to examine the cross-sectional and longitudinal associations of the MetS and components of the MetS to percent MD in 790 premenopausal and early perimenopausal women enrolled in the Study of Women's Health Across the Nation (SWAN). In cross-sectional analyses adjusted for body mass index (BMI), modest inverse associations were observed between percent MD and the MetS [ß = -2.5, standard error (SE) = 1.9, p = 0.19], abdominal adiposity (ß = -4.8, SE = 1.9, p = 0.01) and raised glucose (ß = -3.7, SE = 2.4, p = 0.12). In longitudinal models adjusted for covariates including age and BMI, abdominal adiposity (ß = 0.34, SE = 0.17, p = 0.05) was significantly positively associated with slower annual decline in percent MD with time. In conclusion, our results do not support the hypothesis that the MetS increases breast cancer risk via a mechanism reflected by an increase in percent MD.

Physical activity and change in mammographic density: the Study of Women's Health Across the Nation.

One potential mechanism by which physical activity may protect against breast cancer is by decreasing mammographic density. Percent mammographic density, the proportion of dense breast tissue area to total breast area, declines with age and is a strong risk factor for breast cancer. The authors hypothesized that women who were more physically active would have a greater decline in percent mammographic density with age, compared with less physically active women. The authors tested this hypothesis using longitudinal data (1996-2004) from 722 participants in the Study of Women's Health Across the Nation (SWAN), a multiethnic cohort of women who were pre- and early perimenopausal at baseline, with multivariable, repeated-measures linear regression analyses. During an average of 5.6 years, the mean annual decline in percent mammographic density was 1.1% (standard deviation = 0.1). A 1-unit increase in total physical activity score was associated with a weaker annual decline in percent mammographic density by 0.09% (standard error = 0.03; P = 0.01). Physical activity was inversely associated with the change in nondense breast area (P < 0.01) and not associated with the change in dense breast area (P = 0.17). Study results do not support the hypothesis that physical activity reduces breast cancer through a mechanism that includes reduced mammographic density.

The incidence of venous thromboembolism and its effect on survival among patients with primary bladder cancer.

BACKGROUND: The incidence, risk factors, time course, and impact on survival of venous thromboembolism (VTE) in a large, population-based study of patients with bladder cancer have not been identified previously. METHODS: The California Cancer Registry was merged with the California Patient Discharge Data Set to determine the incidence of VTE in patients with newly diagnosed bladder cancer within a 6-year period. Cox proportional hazards models were used to determine the risk factors for VTE and the effects of VTE on survival. RESULTS: Among 24,861 patients with bladder cancer, the 2-year incidence of VTE was 1.9%. The highest incidence of VTE occurred in the first 6 months regardless of age, sex, race, tumor stage, or histologic subtype. In a multivariate model, significant risk factors for the development of VTE included major surgery, advancing disease stage, and increasing number of comorbidities. Compared with the general population, the 1-year standardized incidence ratio for VTE in the bladder cancer cohort was 5.3 (95% confidence interval, 4.8-5.9). Among patients with bladder cancer, significant risk factors for death included advancing disease stage, increasing comorbidities, African-American race, nontransitional cell carcinoma histology, and the development of VTE. CONCLUSIONS: Patients with bladder cancer had a 1.9% 2-year incidence of VTE. Metastatic disease was the strongest predictor of both VTE and death. It was noteworthy that cancer-associated surgery was associated with a higher risk of VTE, which differed from the results reported from other studies in solid tumors. VTE was a significant predictor of death in the first 2 years.

Venous thromboembolism in patients with acute leukemia: incidence, risk factors, and effect on survival.

A population-based cohort was used to determine the incidence and risk factors associated with development of venous thromboembolism (VTE) among Californians diagnosed with acute leukemia between 1993 to 1999. Principal outcomes were deep vein thrombosis in both the lower and upper extremities, pulmonary embolism, and mortality. Among 5394 cases with acute myelogenous leukemia (AML), the 2-year cumulative incidence of VTE was 281 (5.2%). Sixty-four percent of the VTE events occurred within 3 months of AML diagnosis. In AML patients, female sex, older age, number of chronic comorbidities, and presence of a catheter were significant predictors of development of VTE within 1 year. A diagnosis of VTE was not associated with reduced survival in AML patients. Among 2482 cases with acute lymphoblastic leukemia (ALL), the 2-year incidence of VTE in ALL was 4.5%. Risk factors for VTE were presence of a central venous catheter, older age, and number of chronic comorbidities. In the patients with ALL, development of VTE was associated with a 40% increase in the risk of dying within 1 year. The incidence of VTE in acute leukemia is appreciable, and is comparable with the incidence in many solid tumors.

Thrombotic thrombocytopenic purpura-hemolytic uremic syndrome (TTP-HUS): a 24-year clinical experience with 178 patients.

BACKGROUND: Thrombotic thrombocytopenic purpura and the hemolytic uremic syndrome (TTP-HUS) are related and uncommon disorders with a high fatality and complication rate if untreated. Plasma exchange therapy has been shown to produce high response rates and improve survival in patients with many forms of TTP-HUS. We performed a retrospective cohort study of 178 consecutively treated patients with TTP-HUS and analyzed whether clinical or laboratory characteristics could predict for important short- and long-term outcome measures. RESULTS: Overall 30-day mortality was 16% (n = 27). 171 patients (96%) received plasma exchange as the principal treatment, with a mean of 8 exchanges and a mean cumulative infused volume of 42 +/- 71 L of fresh frozen plasma. The rate of complete response was 65% or 55% depending on whether this was defined by a platelet count of 100,000/microl or 150,000/microl, respectively. The rate of relapse was 18%. The Clinical Severity Score did not predict for 30-day mortality or relapse. The time to complete response did not predict for relapse. Renal insufficiency at presentation was associated with a decreased risk of relapse, with each unit increase in serum creatinine associated with a 40% decreased odds of relapse. 72% of our cohort had an idiopathic TTP-sporadic HUS, while 17% had an underlying cancer, received a solid organ transplant or were treated with a mitomycin-based therapy. The estimated overall 5-year survival was 55% and was significantly better in those without serious underlying conditions. CONCLUSION: Plasma exchange therapy produced both high response and survival rates in this large cohort of patients with TTP-HUS. The Clinical Severity Score did not predict for 30-day mortality or relapse, contrary to our previous findings. Interestingly, the presence of renal insufficiency was associated with a decreased risk of relapse. The most important predictor of mortality was the presence or absence of a serious underlying disorder.

Venous thromboembolism in ovarian cancer.

OBJECTIVE: To determine the incidence, time-course, and risk factors associated with the development of thromboembolism (VTE) in a population-based study of women with ovarian cancer. METHODS: Using the California Cancer Registry, cases diagnosed with ovarian cancer for a 6-year period were identified. These cases were linked with the California Patient Discharge Data Set to determine the incidence of VTE. Proportional hazards modeling was performed to analyze the strength of specified risk factors to predict development of VTE or death within 2 years. RESULTS: Among 13,031 cases with ovarian cancer, 5.2% were diagnosed with a VTE event within 24 months after diagnosis. The cumulative incidence varied from 1.4% among women with local stage disease to 6.7% among women with advanced disease. The person-time incidence rate of VTE decreased over time, with the highest rate noted during the first 3 months. In a multivariate model, significant risk factors for VTE included advancing age, increasing number of chronic comorbid conditions, more advanced cancer stage, invasive histology, and absence of any major surgery. For all stages of cancer, development of VTE within 2 years was a significant risk factor for decreased survival, and the magnitude of the risk was greatest among the cases diagnosed with localized disease (HR 4.7, 95% CI: 2.3-9.5). CONCLUSIONS: VTE occurred in a significant proportion of ovarian cancer patients and adversely impacted survival, particularly among cases with local or regional stage cancer.

Co-morbidity is a strong predictor of early death and multi-organ system failure among patients with acute pancreatitis.

A small but significant percentage of patients with acute pancreatitis die within 2 weeks of hospitalization, usually with multiorgan system failure. To determine the effect of chronic medical comorbidities on early death, we conducted a retrospective analysis of all patients who were hospitalized in California with first-time pancreatitis between 1992 and 2002. Among 84,713 patients, 1514 (1.8%) died within 2 weeks. In a risk-adjusted multivariate model, the strongest predictors of early death were age 65 to 75 years (OR = 2.6, 95% CI: 2.2-3.1 versus <55 years), age over 75 years (OR = 5.2, 95% CI: 4.4-6.1), and the presence of either two chronic comorbid conditions (OR = 3.5, CI: 2.7-4.6) or three or more comorbidities (OR = 7.4, 95% CI: 5.7-9.5). Among the 14,280 patients younger than 55 years who had no chronic comorbid conditions, only 14 (0.1%) died in the first 14 days compared to 701 (5.9%) of 24,852 patients 64 years or older who had three or more comorbidities (RR = 29, 95% CI: 17-50). Comorbid conditions associated with early death included recent cancer, heart failure, renal disease, and liver disease. We conclude that advancing age and the number of chronic comorbid conditions are very strong predictors of early death among patients with acute pancreatitis.