An epidemiologic study comparing cancer- and noncancer-associated venous thromboembolism in a racially diverse Southeastern United States county.

Background: Cancer-associated venous thromboembolism (CA-VTE) represents a major cause of morbidity and mortality in patients with cancer. Despite poor outcomes, there is an ongoing knowledge gap in epidemiologic data related to this association. Objectives: To compare venous thromboembolism (VTE) characteristics, risk factors, and outcomes between patients with and without active cancer in a racially diverse population. Methods: Our surveillance project occurred at the 3 hospitals in Durham County, North Carolina, from April 2012 through March 2014. Electronic and manual methods were used to identify unique Durham County residents with VTE. Results: We identified 987 patients with VTE during the surveillance period. Of these, 189 patients had active cancer at the time of their VTE event. Patients with CA-VTE were older (median age: 69 years vs 60 years, P < .0001) and had a lower body mass index (median body mass index: 26.0 kg/m2 vs 28.4 kg/m2, P = .0001) than noncancer patients. The most common cancers in our cohort were gastrointestinal, breast, genitourinary, and lung. The proportion of VTE cases with pulmonary embolism (PE) was greater in the cancer cohort compared with that in the noncancer cohort (58.2% vs 44.0%, P = .0004). Overall survival was lower in the CA-VTE group than in patients without cancer (P < .0001). Black patients with CA-VTE had lower proportion of PE (52.3% vs 67.1%, P = .05) but had decreased survival (P < .0003) in comparison with White patients. Conclusion: Future studies may be needed to continue to evaluate local and national VTE data to improve VTE prevention strategies and CA-VTE outcomes.

Racial differences in venous thromboembolism: A surveillance program in Durham County, North Carolina.

Background: Venous thromboembolism (VTE) affects approximately 1-2 individuals per 1000 annually and is associated with an increased risk for pulmonary hypertension, postthrombotic syndrome, and recurrent VTE. Objective: To determine risk factors, incidence, treatments, and outcomes of VTE through a 2-year surveillance program initiated in Durham County, North Carolina (population approximately 280,000 at time of study). Patients/Methods: We performed a retrospective analysis of data actively collected from three hospitals in Durham County during the surveillance period. Results: A total of 987 patients were diagnosed with VTE, for an annual rate of 1.76 per 1000 individuals. Hospital-associated VTE occurred in 167 hospitalized patients (16.9%) and 271 outpatients who were hospitalized within 90 days of diagnosis (27.5%). Annual incidence was 1.98 per 1000 Black individuals compared to 1.25 per 1000 White individuals (p < 0.0001), and Black individuals with VTE were younger than White individuals (p < 0.0001). Common risk factors included active cancer, prolonged immobility, and obesity, and approximately half were still taking anticoagulant therapy 1 year later. A total of 224 patients died by 1 year (28.5% of patients for whom outcomes could be confirmed), and Black patients were more likely to have recurrent VTE than White patients during the first 6 months following initial presentation (9.4% vs. 4.1%, p = 0.01). Conclusions: Ongoing surveillance provides an effective strategy to identify patients with VTE and monitor treatment and outcomes. We demonstrated that hospital-associated VTE continues to be a major contributor to the burden of VTE and confirmed the higher incidence of VTE in Black compared to White individuals.

Cancer-associated venous thromboembolism: Incidence and features in a racially diverse population.

BACKGROUND: Data on the population-based incidence of cancer-associated venous thromboembolism (VTE) from racially diverse populations are limited. OBJECTIVE: To evaluate the incidence and burden of cancer-associated VTE, including demographic and racial subgroups in the general population of Oklahoma County-which closely mirrors the United States. DESIGN: A population-based prospective study. SETTING: We conducted surveillance of VTE at tertiary care facilities and outpatient clinics in Oklahoma County, Oklahoma, from 2012-2014. Surveillance included reviewing all imaging reports used to diagnose VTE and identifying VTE events from hospital discharge data and death certificates. Cancer status was determined by linkage to the Oklahoma Central Cancer Registry. MEASUREMENTS: We used Poisson regression to calculate crude and age-adjusted incidence rates of cancer-associated VTE per 100 000 general population per year, with 95% confidence intervals (95% CI). RESULTS: The age-adjusted incidence (95% CI) of cancer-associated VTE among adults age ≥ 18 was 70.0 (65.1-75.3). The age-adjusted incidence rates (95% CI) were 85.9 (72.7-101.6) for non-Hispanic Blacks, 79.5 (13.2-86.5) for non-Hispanic Whites, 18.8 (8.9-39.4) for Native Americans, 15.6 (7.0-34.8) for Asian/Pacific Islanders, and 15.2 (9.2-25.1) for Hispanics. Recurrent VTE up to 2 years after the initial diagnosis occurred in 38 of 304 patients (12.5%) with active cancer and in 34 of 424 patients (8.0%) with a history of cancer > 6 months previously. CONCLUSION: Age-adjusted incidence rates of cancer-associated VTE vary substantially by race and ethnicity. The relatively high incidence rates of first VTE and of recurrence warrant further assessment of strategies to prevent VTE among cancer patients.

Epidemiology of cerebral venous sinus thrombosis and cerebral venous sinus thrombosis with thrombocytopenia in the United States, 2018 and 2019.

Background: Population-based data about cerebral venous sinus thrombosis (CVST) are limited. Objectives: To investigate the epidemiology of CVST in the United States. Patients/Methods: Three administrative data systems were analyzed: the 2018 Healthcare Cost and Utilization Project National Inpatient Sample (NIS) the 2019 IBM MarketScan Commercial and Medicare Supplemental Claims Database, and the 2019 IBM MarketScan Multi-state Medicaid Database. CVST, thrombocytopenia, and numerous comorbidities were identified using the International Classification of Diseases, Tenth Revision, Clinical Modification codes. Incidence rates of CVST and CVST with thrombocytopenia were estimated (per 100,000 total US population [NIS] and per 100,000 population aged 0 to 64 years covered by relevant contributing health plans [MarketScan samples]). Comorbidity prevalence was estimated among CVST cases versus total inpatients in the NIS sample. Recent pregnancy prevalence was estimated for the Commercial sample. Results: Incidence rates of CVST in NIS, Commercial, and Medicaid samples were 2.85, 2.45, and 3.16, respectively. Incidence rates of CVST with thrombocytopenia were 0.21, 0.22, and 0.16, respectively. In all samples, CVST incidence increased with age; however, peak incidence was reached at younger ages in females than males. Compared with the general inpatient population, persons with CVST had higher prevalences of hemorrhagic stroke, ischemic stroke, other venous thromboembolism (VTE), central nervous system infection, head or neck infection, prior VTE, thrombophilia, malignancy, head injury, hemorrhagic disorder, and connective tissue disorders. Women aged 18 to 49 years with CVST had a higher pregnancy prevalence than the same-aged general population. Conclusions: Our findings provide recent and comprehensive data on the epidemiology of CVST and CVST with thrombocytopenia.

Exploring the Applicability of Using Natural Language Processing to Support Nationwide Venous Thromboembolism Surveillance: Model Evaluation Study.

Background: Venous thromboembolism (VTE) is a preventable, common vascular disease that has been estimated to affect up to 900,000 people per year. It has been associated with risk factors such as recent surgery, cancer, and hospitalization. VTE surveillance for patient management and safety can be improved via natural language processing (NLP). NLP tools have the ability to access electronic medical records, identify patients that meet the VTE case definition, and subsequently enter the relevant information into a database for hospital review. Objective: We aimed to evaluate the performance of a VTE identification model of IDEAL-X (Information and Data Extraction Using Adaptive Learning; Emory University)-an NLP tool-in automatically classifying cases of VTE by "reading" unstructured text from diagnostic imaging records collected from 2012 to 2014. Methods: After accessing imaging records from pilot surveillance systems for VTE from Duke University and the University of Oklahoma Health Sciences Center (OUHSC), we used a VTE identification model of IDEAL-X to classify cases of VTE that had previously been manually classified. Experts reviewed the technicians' comments in each record to determine if a VTE event occurred. The performance measures calculated (with 95% CIs) were accuracy, sensitivity, specificity, and positive and negative predictive values. Chi-square tests of homogeneity were conducted to evaluate differences in performance measures by site, using a significance level of .05. Results: The VTE model of IDEAL-X "read" 1591 records from Duke University and 1487 records from the OUHSC, for a total of 3078 records. The combined performance measures were 93.7% accuracy (95% CI 93.7%-93.8%), 96.3% sensitivity (95% CI 96.2%-96.4%), 92% specificity (95% CI 91.9%-92%), an 89.1% positive predictive value (95% CI 89%-89.2%), and a 97.3% negative predictive value (95% CI 97.3%-97.4%). The sensitivity was higher at Duke University (97.9%, 95% CI 97.8%-98%) than at the OUHSC (93.3%, 95% CI 93.1%-93.4%; P<.001), but the specificity was higher at the OUHSC (95.9%, 95% CI 95.8%-96%) than at Duke University (86.5%, 95% CI 86.4%-86.7%; P<.001). Conclusions: The VTE model of IDEAL-X accurately classified cases of VTE from the pilot surveillance systems of two separate health systems in Durham, North Carolina, and Oklahoma City, Oklahoma. NLP is a promising tool for the design and implementation of an automated, cost-effective national surveillance system for VTE. Conducting public health surveillance at a national scale is important for measuring disease burden and the impact of prevention measures. We recommend additional studies to identify how integrating IDEAL-X in a medical record system could further automate the surveillance process.

Evaluation of CDC's Hemophilia Surveillance Program - Universal Data Collection (1998-2011) and Community Counts (2011-2019), United States.

PROBLEM/CONDITION: Hemophilia is an X-linked genetic disorder that primarily affects males and results in deficiencies in blood-clotting proteins. Hemophilia A is a deficiency in factor VIII, and hemophilia B is a deficiency in factor IX. Approximately one in 5,000 males are born with hemophilia, and hemophilia A is about four times as common as hemophilia B. Both disorders are characterized by spontaneous internal bleeding and excessive bleeding after injuries or surgery. Hemophilia can lead to repeated bleeding into the joints and associated chronic joint disease, neurologic damage, damage to other organ systems, and death. Although no precise national U.S. prevalence estimates for hemophilia exist because of the difficulty identifying cases among persons who receive care from various types of health care providers, two previous state-based studies estimated hemophilia prevalence at 13.4 and 19.4 per 100,000 males. In addition, these studies showed that 67% and 82% of persons with hemophilia received care in a federally funded hemophilia treatment center (HTC), and 86% and 94% of those with the most severe cases of hemophilia (i.e., those with the lowest levels of clotting factor activity in the circulating blood) received care in a federally funded HTC. As of January 2020, the United States had 144 HTCs. PERIOD COVERED: 1998-2019. DESCRIPTION OF THE SYSTEM: Surveillance for hemophilia, which is a complex, chronic condition, is challenging because of its low prevalence, the difficulty in ascertaining cases uniformly, and the challenges in routinely characterizing and tracking associated health complications. Over time, two systems involving many stakeholders have been used to conduct ongoing hemophilia surveillance. During 1998-2011, CDC and the HTCs collaborated to establish the Universal Data Collection (UDC) surveillance system. The purposes of the UDC surveillance system were to monitor human immunodeficiency virus (HIV) and bloodborne viral hepatitis in persons with hemophilia, thereby tracking blood safety, and to track the prevalence of and trends in complications associated with hemophilia. HTC staff collected clinical data and blood specimens from UDC participants and submitted them to CDC. CDC tested specimens for viral hepatitis and HIV. In 2011, the UDC surveillance system was replaced by a new hemophilia surveillance system called Community Counts. CDC and the HTCs established Community Counts to expand laboratory testing and the collection of clinical data to better identify and track emerging health issues in persons with hemophilia. RESULTS: This report is the first comprehensive summary of CDC's hemophilia surveillance program, which comprises both UDC and Community Counts. Data generated from these surveillance systems have been used in the development of public health and clinical guidelines and practices to improve the safety of U.S. blood products and either prevent hemophilia-related complications or identify complications early. Several factors have played a role in the effectiveness of the UDC and Community Counts systems, including 1) a stable data collection design that was developed and is continually reviewed in close partnership with HTC regional leaders and providers to ensure surveillance activities are focused on maximizing the scientific and clinical impact; 2) flexibility to respond to emerging health priorities through periodic updates to data collection elements and special studies; 3) high data quality for many clinical indicators and state-of-the-art laboratory testing methods for hemophilia treatment product inhibitors (developed and refined in part based on CDC research); 4) timely data and specimen collection and submission, laboratory specimen testing, analysis, and reporting; and 5) the largest and most representative sample of persons with hemophilia in the United States and one of the largest and most comprehensive data collection systems on hemophilia worldwide. INTERPRETATION: CDC has successfully developed, implemented, and maintained a surveillance system for hemophilia. The program can serve as an example of how to conduct surveillance for a complex chronic disease by involving stakeholders, improving and building new infrastructure, expanding data collection (e.g., new diagnostic assays), providing testing guidance, establishing a registry with specimen collection, and integrating laboratory findings in clinical practice for the individual patient. PUBLIC HEALTH ACTION: Hemophilia is associated with substantial lifelong morbidity, excess premature deaths, and extensive health care needs throughout life. Through monitoring data from Community Counts, CDC will continue to characterize the benefits and adverse events associated with existing or new hemophilia treatment products, thereby contributing to maximizing the health and longevity of persons with hemophilia.

Predictive accuracy of 29-comorbidity index for in-hospital deaths in US adult hospitalizations with a diagnosis of venous thromboembolism.

BACKGROUND: Venous thromboembolism (VTE), comprising deep vein thrombosis (DVT) and pulmonary embolism (PE), is a significant source of mortality and morbidity worldwide. By analyzing data of the 2010 Nationwide Inpatient Sample from the Agency for Healthcare Research and Quality (AHRQ), we evaluated the predictive accuracy of the AHRQ's 29-comorbidity index with in-hospital death among US adult hospitalizations with a diagnosis of VTE. METHODS: We assessed the case-fatality and prevalence of comorbidities among a sample of 153,518 adult hospitalizations with a diagnosis of VTE that comprised 87,605 DVTs and 65,913 PEs (with and without DVT). We estimated adjusted odds ratios and 95% confidence intervals with multivariable logistic regression models by using comorbidities as predictors and status of in-hospital death as an outcome variable. We assessed the c-statistics for the predictive accuracy of the logistic regression models. RESULTS: In 2010, approximately 41,944 in-hospital deaths (20,212 with DVT and 21,732 with PE) occurred among 770,137 hospitalizations with a diagnosis of VTE. When compared separately to hospitalizations with VTE, DVT, or PE that had no corresponding comorbidities, congestive heart failure, chronic pulmonary disease, coagulopathy, liver disease, lymphoma, fluid and electrolyte disorders, metastatic cancer, other neurological disorders, peripheral vascular disorders, pulmonary circulation disorders, renal failure, solid tumor without metastasis, and weight loss were positively and independently associated with 10%-125% increased likelihoods of in-hospital death. The c-statistic values ranged from 0.776 to 0.802. CONCLUSION: The results of this study indicated that comorbidity was associated independently with risk of death among hospitalizations with VTE and among hospitalizations with DVT or PE. The AHRQ 29-comorbidity index provides acceptable to excellent predictive accuracy for in-hospital deaths among adult hospitalizations with VTE and among those with DVT or PE.

Late preterm birth and risk of developing asthma.

OBJECTIVE: To evaluate the association between gestational age at birth (late preterm vs term) and risk for physician-diagnosed asthma. STUDY DESIGN: We conducted a retrospective cohort study using the Third National Health and Nutrition Examination Survey (1988-1994) linked natality files. The study included children age 2-83 months from singleton births, born late preterm (n=537) or term (n=5650). Using survival analysis, we modeled time to diagnosis of asthma; children with no asthma diagnosis were censored at the age of their survey interview. We used Cox proportional hazard regression to estimate hazard ratios and 95% confidence intervals for gestational age and asthma risk, adjusting for maternal age, maternal education, parental history of asthma/hay fever, maternal smoking history during pregnancy, race/ethnicity, and sex of the child. RESULTS: Adjusted analysis showed that physician-diagnosed asthma was modestly associated with late preterm birth (hazard ratio, 1.3; 95% confidence interval, 0.8-2.0), but this association was not statistically significant (P=.30). CONCLUSIONS: Our study found that late preterm birth was not associated with a diagnosis of asthma in early childhood.

Outbreak of Burkholderia cepacia bloodstream infection at an outpatient hematology and oncology practice.

We investigated an outbreak of infection in 10 patients with blood cultures positive for B. cepacia. All patients had indwelling intravenous catheters. Though we did not identify the source of the organism, our findings support the hypothesis that cross-contamination of multidose medications through the use of the same needle and syringe was a contributing factor.

Fas-associated protein with death domain (FADD)-independent recruitment of c-FLIPL to death receptor 5.

Here we show a novel mechanism by which FLICE-like inhibitory protein (c-FLIP) regulates apoptosis induced by tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) and one of its receptors, DR5. c-FLIP is a critical regulator of the TNF family of cytokine receptor signaling. c-FLIP has been postulated to prevent formation of the competent death-inducing signaling complex (DISC) in a ligand-dependent manner, through its interaction with FADD and/or caspase-8. In order to identify regulators of TRAIL function, we used the intracellular death domain (DD) of DR5 as a target to screen a phage-displayed combinatorial peptide library. The DD of DR5 selected from the library a peptide that showed sequence similarity to a stretch of amino acids in the C terminus of c-FLIP(L). The phage-displayed peptide selectively interacted with the DD of DR5 in in vitro binding assays. Similarly, full-length c-FLIP (c-FLIP(L)) and the C-terminal p12 domain of c-FLIP interacted with DR5 both in in vitro pull-down assays and in mammalian cells. This interaction was independent of TRAIL. To the contrary, TRAIL treatment released c-FLIP(L) from DR5, permitting the recruitment of FADD to the active DR5 signaling complex. By employing FADD-deficient Jurkat cells, we demonstrate that DR5 and c-FLIP(L) interact in a FADD-independent manner. Moreover, we show that a cellular membrane permeable version of the peptide corresponding to the DR5 binding domain of c-FLIP induces apoptosis in mammalian cells. Taken together, these findings indicate that c-FLIP interacts with the DD of DR5, thus preventing death (L)signaling by DR5 prior to the formation of an active DISC. Because TRAIL and DR5 are ubiquitously expressed, the interaction of c-FLIP(L) and DR5 indicates a mechanism by which tumor selective apoptosis can be achieved through protecting normal cells from undergoing death receptor-induced apoptosis.

Vav transformation requires activation of multiple GTPases and regulation of gene expression.

Although Vav can act as a guanine nucleotide exchange factor for RhoA, Rac1, and Cdc42, its transforming activity has been ascribed primarily to its ability to activate Rac1. However, because activated Vav, but not Rac-specific guanine nucleotide exchange factors, exhibits very potent focus-forming transforming activity when assayed in NIH 3T3 cells, Vav transforming activity must also involve activation of Rac-independent pathways. In this study, we determined the involvement of other Rho family proteins and their signaling pathways in Vav transformation. We found that RhoA, Rac1, and Cdc42 functions are all required for Vav transforming activity. Furthermore, we determined that Vav activation of nuclear factor-kappaB and the Jun NH2-terminal kinase mitogen-activated protein kinase (MAPK) is necessary for full transformation by Vav, whereas p38 MAPK does not seem to play an important role. We also determined that Vav is a weak activator of Elk-1 via a Ras- and MAPK/extracellular signal-regulated kinase kinase-dependent pathway, and this activity was essential for Vav transformation. Thus, we conclude that full Vav transforming activation is mediated by the activation of multiple small GTPases and their subsequent activation of signaling pathways that regulate changes in gene expression. Because Vav is activated by the epidermal growth factor receptor and other tyrosine kinases involved in cancer development, defining the role of aberrant Vav signaling may identify activities of receptor tyrosine kinases important for human oncogenesis.

Critical role of the pleckstrin homology and cysteine-rich domains in Vav signaling and transforming activity.

Vav family proteins are members of the Dbl family of guanine nucleotide exchange factors and activators of Rho family small GTPases. In addition to the Dbl homology (DH) domain important for guanine nucleotide exchange factor catalytic function, all Dbl family proteins contain an adjacent pleckstrin homology (PH) domain that serves to regulate DH domain activity. Although the role of the PH domain in Vav function has been evaluated extensively, its precise role and whether it serves a distinct role in different Vav proteins remain unresolved. Additionally, the precise role of an adjacent cysteine-rich domain (CRD) in regulating DH domain function is also unclear. In this study, we evaluated the contribution of these putative protein-protein or protein-lipid interaction domains to Vav signaling and transforming activity. In contrast to previous observations, we found that the PH domain is critical for Vav transforming activity. Similarly, the CRD was also essential and served a function distinct from that of the PH domain. Although mutation of either domain reduced Vav membrane association, addition of plasma membrane targeting sequences to either the CRD or PH domain mutant proteins did not restore Vav transforming activity. This result contrasts with other Dbl family proteins, where a membrane targeting sequence alone was sufficient to restore the loss of function caused by mutation of the PH domain. Furthermore, green fluorescent protein fusion proteins containing the PH domain or CRD, or both, failed to target to the plasma membrane, suggesting that these two domains also serve regulatory functions independent of promoting membrane localization. Finally, we found that phosphatidylinositol 3-kinase activation may promote Vav membrane association via phosphatidylinositol 3,4,5-triphosphate binding to the PH domain.