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Data on the population-based incidence of cancer-associated venous thromboembolism (VTE) from racially diverse populations are limited.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.A population-based prospective study.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.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).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 cancergt; 6 months previously.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.

Sickle cell disease (SCD) is associated with increased risk of poor health outcomes from respiratory infections, including COVID-19 illness. We used US death data to investigate changes in SCD-related mortality before and during the COVID-19 pandemic. We estimated annual age- and quarter-adjusted SCD-related mortality rates for 2014-2020. We estimated the number of excess deaths in 2020 compared with 2019 using the standardized mortality ratio (SMR). We found 1023 SCD-related deaths reported in the United States during 2020, of which 86 (8.4%) were associated with COVID-19. SCD-related deaths, both associated and not associated with COVID-19, occurred most frequently among adults aged 25-59 years. The SCD-related mortality rate changed

Sickle cell disease (SCD), an inherited blood disorder affecting an estimated 100,000 persons in the United States, is associated with multiple complications and reduced life expectancy. Complications of SCD can include anemia, debilitating acute and chronic pain, infection, acute chest syndrome, stroke, and progressive organ damage, including decreased cognitive function and renal failure. Early diagnosis, screenings and preventive interventions, and access to specialist health care can decrease illness and death. Population-based public health surveillance is critical to understanding the course and outcomes of SCD as well as the health care use, unmet health care needs, and gaps in essential services of the population affected by SCD.2004-2018.In 2015, CDC established the Sickle Cell Data Collection (SCDC) program to characterize the epidemiology of SCD in two states (California and Georgia). Previously, surveillance for SCD was conducted by two short-term projects: Registry and Surveillance System for Hemoglobinopathies (RuSH), which was conducted during 2010-2012 and included 2004-2008 data, and Public Health Research, Epidemiology, and Surveillance for Hemoglobinopathies (PHRESH), which was conducted during 2012-2014 and included 2004-2008 data. Both California and Georgia participated in RuSH and PHRESH, which guided the development of the SCDC methods and case definitions. SCDC is a population-based tracking system that uses comprehensive data linkages in state health systems. These linkages serve to synthesize and disseminate population-based, longitudinal data for persons identified with SCD from multiple sources using selected International Classification of Diseases, Ninth Revision, Clinical Modification, and Tenth Revision codes and laboratory results confirmed through state newborn screening (NBS) programs or clinic case reporting. Administrative and clinical data sources include state Medicaid and Children's Health Insurance Program databases, death certificates, NBS programs, hospital discharge and emergency department records, and clinical records or case reports. Data from multiple sources and years are linked and deduplicated so that states can analyze and report on SCD population prevalence, demographic characteristics, health care access and use, and health outcomes. The SCD case definition is based on an algorithm that classifies cases with laboratory confirmation as confirmed cases and those with a reported clinical diagnosis or three or more diagnostic codes over a 5-year period from an administrative data source as probable cases. In 2019, nine states (Alabama, California, Georgia, Indiana, Michigan, Minnesota, North Carolina, Tennessee, and Virginia) were funded as part of an SCDC capacity-building initiative. The newly funded states developed strategies for SCD case identification and data linkage similar to those used by California and Georgia. As of 2021, the SCDC program had expanded to 11 states with the addition of Colorado and Wisconsin.During 2004-2018, the cumulative prevalence of confirmed and probable SCD cases identified in California and Georgia was 9,875 and 14,777 cases, respectively. The 2018 annual prevalence count was 6,027 cases for California and 9,141 for Georgia. Examination of prevalence counts by contributing data source during 2014-2018 revealed that each data source captured 16%-71% of cases in California and 17%-87% in Georgia; therefore, no individual source is sufficient to estimate statewide population prevalence. The proportion of pediatric SCD patients (children aged 0-18 years) was 27% in California and 40% in Georgia. The percentage of females with SCD in California and Georgia was 58% and 57%, respectively. Of the cases with SCD genotyping data available (n = 5,856), 63% of patients had sickle cell anemia. SCDC data have been used to directly apprise health care providers and policymakers about health care needs and gaps for patients with SCD. For example, an SCDC Georgia assessment indicated that 10% of babies born during 2004-2016 with SCD lived more than a 1-hour drive from any SCD specialty care option, and another 14% lived within a 1-hour drive of a periodic SCD specialty clinic only. Likewise, an SCDC California assessment indicated that during 2016-2018, most patients with SCD in Los Angeles County lived approximately 15-60 miles from hematologists experienced in SCD care. A surveillance capacity and performance assessment of all 11 SCDC states during 2020-2021 indicated that states differed in the availability of data sources used for SCD surveillance and the time frames for accessing each state data source. Nonetheless, methods for standardizing reporting were developed across all participating states.This report is the first comprehensive description of CDC's efforts in collaboration with participating states to establish, maintain, and expand SCD surveillance through the SCDC program to improve health outcomes for persons living with SCD. Findings from California and Georgia analyses highlighted a need for additional SCD specialty clinics. Despite different approaches, expansion of SCDC to multiple states was possible using standardized, rigorous methods developed across all participating states for reporting on disease prevalence, health care needs and use, and deaths.Findings from surveillance can be used to improve and monitor care and outcomes for persons with SCD. These and other SCDC analyses have had a role in opening new SCD clinics, educating health care providers, developing state health care policies, and guiding new research initiatives. Public health officials can use this report as a guiding framework to plan or implement surveillance programs for persons with SCD. Both data-related activities (data sources; patient identifiers; and obtaining, transferring, and linking data) and the administrative considerations (stakeholder engagement, costs and resources, and long-term sustainability) are crucial to the success of these programs.

Sickle cell disease (SCD), a group of inherited blood cell disorders that primarily affects Black or African American persons, is associated with severe complications and a20-year reduction in life expectancy. In 2014, an expert panel convened by the National Heart, Lung, and Blood Institute issued recommendations to prevent or reduce complications in children and adolescents with the most severe SCD subtypes, known as sickle cell anemia (SCA); recommendations included 1) annual screening of children and adolescents aged 2-16 years with transcranial Doppler (TCD) ultrasound to identify those at risk for stroke and 2) offering hydroxyurea therapy to children and adolescents aged ≥9 months to reduce the risk for several life-threatening complications.Data from the IBM MarketScan Multi-State Medicaid Database were analyzed. TCD screening and hydroxyurea use were examined for 3,352 children and adolescents with SCA aged 2-16 years and continuously enrolled in Medicaid during 2019. Percentage change during 2014-2019 and variation by health subgroups were assessed. Analyses were stratified by age.During 2014-2019, TCD screening increased 27% among children and adolescents aged 10-16 years; hydroxyurea use increased 27% among children aged 2-9 years and 23% among children and adolescents aged 10-16 years. However, in 2019, only 47% and 38% of children and adolescents aged 2-9 and 10-16 years, respectively, had received TCD screening and 38% and 53% of children and adolescents aged 2-9 years and 10-16 years, respectively, used hydroxyurea. For both prevention strategies, usage was highest among children and adolescents with high levels of health care utilization and evidence of previous complications indicative of severe disease.Despite increases since 2014, TCD screening and hydroxyurea use remain low among children and adolescents with SCA. Health care providers should implement quality care strategies within their clinics and partner with patients, families, and community-based organizations to address barriers to delivering and receiving recommended care.

Upon request from tribal nations, and as part of the Centers for Disease Control and Prevention’s (CDC’s) emergency response, CDC staff provided both remote and on-site assistance to tribes to plan, prepare, and respond to the COVID-19 pandemic. From April 2, 2020, through June 11, 2021, CDC deployed a total of 275 staff to assist 29 tribal nations. CDC staff typically collaborated in multiple work areas including epidemiology and surveillance (86%), contact tracing (76%), infection prevention control (72%), community mitigation (72%), health communication (66%), incident command structure (55%), emergency preparedness (38%), and worker safety (31%). We describe the activities of CDC staff in collaboration with 4 tribal nations, Northern Cheyenne, Hoopa Valley, Shoshone-Bannock, and Oglala Sioux Tribe, to combat COVID-19 and lessons learned from the engagement.

BACKGROUND Conducting public health surveillance for venous thromboembolism (VTE) at a national scale is important for measuring the disease burden and the impact of prevention measures. Integrating natural language processing (NLP) into VTE surveillance may be an efficient and accurate option in establishing a sustainable and cost-effective national surveillance system. OBJECTIVE We evaluated the performance of the VTE identification instance of IDEAL-X, an NLP tool, in automatically classifying cases of VTE from “reading” unstructured text from diagnostic imaging records. METHODS Accessing imaging records from pilot surveillance systems for VTE from Duke University and the University of Oklahoma Health Sciences Center (OUHSC) during 2012–2014, we used a VTE identification model of IDEAL-X to classify cases of VTE that had previously been manually classified according to pre-defined criteria. The performance measures (and 95% confidence intervals [CI]) calculated were accuracy, sensitivity, specificity, and positive and negative predictive values. RESULTS The VTE model of IDEAL-X “read” 1591 records from Duke University and 1487 records from 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%), 92.0% specificity (95% CI: 91.9%–92.0%), 89.1% positive predictive value (95% CI: 89.0%–89.2%), and 97.3% negative predictive value (95% CI: 97.3%–97.4%). The sensitivity was higher at Duke University (97.9%, 95% CI: 97.8%–98.0%) than at OUHSC (93.8%, 95% CI: 93.5%–94.0%), but the specificity was higher at OUHSC (96.3%, 95% CI: 96.2%–96.3%) than at Duke University (90.4%, 95% CI: 90.1%–90.5%). CONCLUSIONS The VTE model of IDEAL-X accurately classified cases of VTE from pilot surveillance systems from 2 separate states and health systems. NLP is a promising tool in the design and implementation of an automated national surveillance system for VTE.

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.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).We performed a retrospective analysis of data actively collected from three hospitals in Durham County during the surveillance period.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 (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.

Population-based data about cerebral venous sinus thrombosis (CVST) are limited.To investigate the epidemiology of CVST in the United States.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.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.Our findings provide recent and comprehensive data on the epidemiology of CVST and CVST with thrombocytopenia.

Data on infants and toddlers (ITs) with von Willebrand disease (VWD) are lacking. We used data collected in the US Hemophilia Treatment Center Network (USHTCN) to describe birth characteristics, bleeding episodes, and complications experienced by 105 patients with VWD who were

Introduction In the network of U.S. comprehensive haemophilia treatment centres (HTCs), von Willebrand disease (VWD) is the most common bleeding disorder other than haemophilia. Estimates of the size and characteristics of the VWD population receiving treatment are useful for healthcare planning. Aim Estimate the prevalence and incidence of VWD among males and females receiving care at U.S. HTCs (HTC-treated prevalence and incidence). Methods During the period 2012-2019, de-identified surveillance data were collected on all VWD patients who visited an HTC including year of birth, sex, race, Hispanic ethnicity, VWD type, and laboratory findings and used to calculate period HTC-treated prevalence by VWD type and sex. Data from patients born 1995-1999 were used to estimate HTC-treated incidence rates. Results During the period, 24,238 patients with a diagnosis of VWD attended HTCs; for 23,479 (96.9%), VWD type was reported or could be assigned. Age-adjusted HTC-treated prevalence was 8.6 cases/100,000 (7.2/100,000 for Type 1, 1.2/100,000 for Type 2 and 1.7/million for Type 3) and was twice as high in women as men (4.8 vs. 2.4 cases/100,000) for Type 1 and similar by sex for Type 2 and Type 3. HTC-treated Type 1 incidence increased over the period, averaging nearly threefold higher for women than men (26.2 vs. 9.9/100,000 live births). Sex differences were less for Type 2 (2.2 vs. 1.4 cases/100,000 births) and slight in Type 3. Conclusion Prevalence and incidence of HTC-treated VWD differ by sex and type and are likely strongly influenced by differences in rates of diagnosis.

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.

There are limited observational studies among children diagnosed with von Willebrand Disease (VWD). We analyzed differences in bleeding characteristics by sex and type of VWD using the largest reported surveillance database of children with VWD (n = 2712), ages 2 to 12 years old. We found that the mean ages of first bleed and diagnosis were lowest among children with type 3 VWD. It was even lower among boys than girls among all VWD types, with statistically significant difference among children with type 1 or type 3 VWD. Children with type 3 VWD also reported higher proportions of ever having a bleed compared to other VWD types, with statistically higher proportions of boys compared to girls reporting ever having a bleed with type 1 and type 2 VWD. A similar pattern was observed with the use of treatment product, showing higher usage among type 3 VWD, and among boys than girls with type 1 and type 2 VWD. While there were no differences in life quality or in well-being status by sex, children with type 3 VWD showed a greater need for mobility assistance compared to children with type 1 and type 2 VWD. In an adjusted analysis among children with type 1 VWD, boys showed a significant association of ever bleeding [hazard ratio 1.4; P-value

In the U.S., deaths due to pulmonary embolism (PE) account for 9.2% of all pregnancy-related deaths or approximately 1.5 deaths per 100,000 live births. Maternal deaths and maternal morbidity due to PE are more common among women who deliver by cesarean section. In the past decade, the clinical community has increasingly adopted venous thromboembolism (VTE) guidelines and thromboprophylaxis recommendations for pregnant women. Although deep vein thrombosis rates have decreased during this time-period, PE rates have remained relatively unchanged in pregnancy hospitalizations and as a cause of maternal mortality. Changes in the health profile of women who become pregnant, particularly due to maternal age and co-morbidities, needs more attention to better understand the impact of VTE risk during pregnancy and the postpartum period.

BACKGROUND: Care for infants born preterm or with major birth defects is costly. Specific estimates of financial burden for different payers are lacking, in part because use of administrative data to identify preterm infants and costs is challenging. METHODS: We used private health insurance claims data and billing codes to identify live births during 2013 and calculated first-year expenditures for employer-sponsored health plans for infants born preterm, both overall and stratified by major birth defects. RESULTS: We conservatively estimated that 7.7% of insured infants born preterm accounted for 37% of $2.0 billion spent by participating plans on the care of infants born during 2013. With a mean difference in plan expenditures of ∼$47 100 per infant, preterm births cost the included plans an extra $600 million during the first year of life. Extrapolating to the national level, we projected aggregate employer-sponsored plan expenditures of $6 billion for infants born preterm during 2013. Infants with major birth defects accounted for 5.8% of preterm births but 24.5% of expenditures during infancy. By using an alternative algorithm to identify preterm infants, it was revealed that incremental expenditures were higher: $78 000 per preterm infant and $14 billion nationally. CONCLUSION Preterm births (especially in conjunction with major birth defects) represent a substantial burden on payers, and efforts to mitigate this burden are needed. In addition, researchers need to conduct studies using linked vital records, birth defects surveillance, and administrative data to accurately and longitudinally assess per-infant costs attributable to preterm birth and the interaction of preterm birth with major birth defects.

Introduction: Venous thromboembolism (VTE), defined as deep vein thrombosis (DVT), pulmonary embolism (PE), or both, represents a major cause of morbidity and mortality in patients with cancer. VTE is the second leading cause of death in patients with cancer, after cancer itself, in the United States. Previous studies have suggested differences by race in the occurrence of VTE among cancer patients. The purpose of this study was to investigate clinical differences in black and white patients with VTE and cancer. Methods: We conducted an analysis of a CDC/Duke VTE surveillance project at the three hospitals in Durham County, North Carolina (Duke University Hospital, Duke Regional Hospital and the Durham VA Medical Center) from April 2012 through March 2014. A combination of electronic and manual review methods were used to identify unique Durham County residents with new diagnoses of objectively confirmed VTE. Data abstracted included demographics, risk factors including cancer, clinical data, treatment, and outcomes. Results: A total of 1028 patients with a new VTE were identified during the surveillance period. Twenty-seven patients who were not black or white (e.g., race not listed; Asian; etc), and 41 with VTE affecting areas other than PE or limb DVT (e.g., cerebral sinus venous thrombosis) were excluded from this analysis. Of the remaining 960 patients, slightly more than half were female (497/960=51.8%), more than half were black (508/960=52.9%), almost a third were obese (337/960 = 35.1%), and median age was 59 years old. At the time of their VTE diagnosis, 184 patients with VTE (19.2%) had active cancer, defined as metastatic or diagnosed within the previous 6 months. The proportion of VTE associated with cancer varied by race. Among the 508 black patients with VTE, 111 (21.9%) had active cancer; in comparison, among the 452 white patients with VTE, 73 (16.1%) had active cancer (p-value=0.025). Black patients with VTE and cancer were older, had a lower body mass index (BMI), and were less likely to have sustained a prior VTE compared to black patients with VTE who did not have cancer (Table 1). Similarly, white patients with VTE and cancer had a lower BMI than white patients without cancer (Table 1). However, in contrast to the findings for black patients, white patients with VTE and cancer were not significantly older and did not show differences in having a prior VTE than white patients with VTE who did not have cancer. Additionally, white patients with VTE and cancer were much more likely to have sustained a PE, with or without DVT, and less likely to have sustained a DVT alone, than white patients with VTE who did not have cancer (Table 1). Black and white patients with both VTE and cancer, were similar in several aspects; however, white patients were less likely to have sustained a DVT alone and more likely to have sustained a PE, with or without DVT, compared to black patients. The types of cancer most frequently encountered in black patients with VTE were gastrointestinal (24.3%), genitourinary (23.4%), and lung (18.9%), followed by breast (8.1%), gynecologic (9.0%) and hematologic malignancies (9.9%). The types of cancer most frequently encountered in white patients with VTE were lung (27.4%), breast (16.4%), and gastrointestinal (13.7%), followed by genitourinary (9.6%), gynecologic (8.2%) and hematologic malignancies (6.8%). Black and white patients with VTE and cancer were treated similarly to black and white patients with VTE who did not have cancer, with most receiving anticoagulant therapy and fewer than 10% receiving an IVC filter (Table 1). Enoxaparin was used most frequently, followed by warfarin. Conclusions: There are several notable demographic and clinical differences between patients with VTE with and without cancer. While differences were observed for both black and white patients, several factors that were variable according to cancer status were unique to either black patients or white patients. One notable difference between black and white patients with both VTE and cancer was a lower proportion of DVT only and a higher proportion of PE, with or without DVT, in white patients. Disclosures Ortel: Instrumentation Laboratories: Consultancy.

e13088 Background: Venous thromboembolism (VTE) is a common complication in cancer patients, but contemporary data on the incidence and characteristics of cancer-associated VTE in different racial populations is limited. We sought to measure the incidence rate and characteristics of cancer-associated VTE in a racially diverse population. Methods: We performed a prospective, population–based cohort study of VTE in Oklahoma County, OK during April 1, 2012–March 31, 2014. Surveillance staff regularly visited all tertiary care and relevant outpatient facilities in the county and reviewed the text from all imaging results of chest computed tomography or magnetic resonance imaging, lung perfusion scans, and ultrasound of the extremities to identify cases of VTE. Data on patient characteristics were collected from the electronic medical record. VTE was considered cancer-associated if the patient had a history of cancer other than basal or squamous cell skin cancer. Cancer was defined as “active” if metastatic or diagnosed within 6 months prior to VTE. Associations and incidence were calculated using the chi-square test and Poisson regression, respectively. Results: Of 3,255 patients with ≥1 VTE event (deep-vein thrombosis and/or pulmonary embolism), 732 (23%) had a history of cancer, of whom 309 had active cancer. The types of cancer varied widely. The age-adjusted incidence of cancer-associated VTE was 648 per 100,000 adult population (age ≥ 18). Incidence increased with each decade of age. The racial/ethnic-specific incidence rates were as follows (each per 100,000): Whites non-hispanic (607), Blacks non-Hispanic (557), Native Americans (128), Asian/Pacific Islanders (113) and Hispanics (70). Risk factors for VTE among the 732 with cancer-associated VTE included previous VTE (19%), hospitalization (37%), surgery (33%), and central venous catheter (22%). Of those with a history of cancer ≥ 6 months previously, 32% had no other identifiable VTE risk factor. Conclusions: Cancer-associated VTE comprised about 20-25% of the total population burden of VTE. The incidence varied substantially by race/ethnicity. An appreciable proportion of those with a history of cancer ≥ 6 months previously subsequently developed VTE in the absence of other risk factors.

Objectives The study objective was to examine the prevalence of maternal multivitamin use and associations with preterm birth (

One of the major goals of researchers in the field of apoptosis is to understand the molecular mechanisms of the various components of the apoptotic pathways, with the hope to identify targets for novel cancer therapies. The discovery of a TNF-related, apoptosis-inducing ligand, TRAIL, that kills transformed cells with great specificity in vitro, has provided the hope that TRAIL may be used to induce cell death in tumor cells without affecting normal tissues. However, TRAIL signaling is very complex and a clear understanding of its function is necessary before it can be used in cancer therapy. Complexity of TRAIL-induced signaling is apparent from its ubiquitous expression, its ability to interact with five receptors, and its tumor-selective induction of apoptosis. The signaling events that mediate the tumor selectivity of TRAIL-induced apoptosis and the biological functions of each of the TRAIL receptors are not well characterized. This review will focus on the complexity of TRAIL and the role of c-FLIP in mediating TRAIL function.

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-κB 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.

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.

Perinatal morbidity and mortality are key indicators of a nation's health status. These measures of our nation's health are influenced by decisions made in health care facilities and by health care providers. As our health systems and health care for women and infants can be improved, there is an expectation that these measures of health will also improve. State-based perinatal quality collaboratives (PQCs) are networks of perinatal care providers including hospitals, clinicians, and public health professionals working to improve pregnancy outcomes for women and newborns through continuous quality improvement. Members of the collaborative are healthcare facilities, primarily hospitals, which identify processes of care that require improvement and then use the best available methods to effect change and improve outcomes as quickly as possible. The Division of Reproductive Health at the Centers for Disease Control and Prevention is collaborating with state-based PQCs to enhance their ability to improve perinatal care by expanding the range of neonatal and maternal health issues addressed and including higher proportions of participating hospitals in their state PQC. The work of PQCs is cross-cutting and demonstrates how partnerships can act to translate evidence-based science to clinical care.

Dbs was identified initially as a transforming protein and is a member of the Dbl family of proteins (20 mammalian members). Here we show that Dbs, like its rat homolog Ost and the closely related Dbl, exhibited guanine nucleotide exchange activity for the Rho family members RhoA and Cdc42, but not Rac1, in vitro. Dbs transforming activity was blocked by specific inhibitors of RhoA and Cdc42 function, demonstrating the importance of these small GTPases in Dbs-mediated growth deregulation. Although Dbs transformation was dependent upon the structural integrity of its pleckstrin homology (PH) domain, replacement of the PH domain with a membrane localization signal restored transforming activity. Thus, the PH domain of Dbs (but not Dbl) may be important in modulating association with the plasma membrane, where its GTPase substrates reside. Both Dbs and Dbl activate multiple signaling pathways that include activation of the Elk-1, Jun, and NF-kappaB transcription factors and stimulation of transcription from the cyclin D1 promoter. We found that Elk-1 and NF-kappaB, but not Jun, activation was necessary for Dbl and Dbs transformation. Finally, we have observed that Dbl and Dbs regulated transcription from the cyclin D1 promoter in a NF-kappaB-dependent manner. Previous studies have dissociated actin cytoskeletal activity from the transforming potential of RhoA and Cdc42. These observations, when taken together with those of the present study, suggest that altered gene expression, and not actin reorganization, is the critical mediator of Dbl and Rho family protein transformation.

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.

Rab proteins typically lack the consensus carboxyl-terminal CXXX motif that signals isoprenoid modification of Ras and other isoprenylated proteins and, instead, terminate in either CC or CXC sequences (C = cysteine, X = any amino acid). To compare the functional relationship between the Ras CXXX and the Rab CC/CXC motifs, we have generated chimeric Ras proteins terminating in Rab carboxyl-terminal CC or CXC sequences. These mutant Ras proteins were not isoprenylated in vitro or in vivo, demonstrating that the CC and CXC sequences alone are not sufficient to replace a CXXX sequence to signal Ras isoprenoid modification. Surprisingly, chimeric Ras/Rab proteins terminating in significant lengths of carboxyl-terminal sequences from Rab1b (7-139 residues), Rab2 (5-151 residues), or Rab3a (12 residues) were also not isoprenylated. These results demonstrate that the sequence requirements for isoprenoid modification of Rab proteins are more complex than the simple tetrapeptide CXXX sequence for isoprenoid modification of Ras proteins and suggest that the Rab geranylgeranyl transferase(s) requires recognition of protein conformation to signal the addition of geranylgeranyl groups. Finally, competition studies demonstrate that a common geranylgeranyl transferase activity is responsible for the modification of Rab proteins terminating in CC or CXC motifs.

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.

Objective To estimate the prevalence of gestational diabetes mellitus (GDM) prevalence estimates for subgroups of US Asian and Pacific Islander (API) women by using data from 2005 and 2006 birth certificates. Methods Using 2005–2006 natality files from states that implemented the revised 2003 US birth certificate, which differentiates between GDM and preexisting diabetes (2005: 12 states; 2006: 19 states), we calculated age-adjusted GDM prevalence estimates for API mothers who delivered singleton infants. Results Among 3,108,877 births, US APIs had a substantially higher age-adjusted prevalence of GDM (6.3%) than whites (3.8%), blacks (3.5%), or Hispanics (3.6%). Among API subgroups, age-adjusted GDM prevalence varied significantly, from 3.7% among women of Japanese descent to 8.6% among women of Asian Indian descent. Foreign-born APIs had significantly higher GDM rates than US-born APIs except among women of Japanese and Korean ancestry. Conclusion Overall, US API women have the highest risk for GDM among all US racial/ethnic groups. However, APIs are a heterogeneous group by genetic background, culture, and diet and other lifestyle behaviors. Our findings imply that, whenever possible, API subgroups should be evaluated separately in health research.

Preterm birth is one of the leading causes of infant mortality and the leading cause of infant morbidity in the United States. It accounts for70% of neonatal deaths and almost half of long-term neurological disabilities. The Centers for Disease Control and Prevention (CDC) is collaborating with state health departments, universities, communities, and healthcare providers to understand why preterm births occur and how to address preterm birth risk factors. These collaborations include identification of genetic and other biological markers for the early detection of women at high risk of preterm birth; improving understanding of the relationships among psychosocial stress, immune and inflammatory responses, and preterm risk; and designing community strategies to improve the health of pregnant women. By conducting public health research activities that explore the genetic, biological, clinical, behavioral, social, and community determinants of preterm birth, CDC will continue to elucidate the complex interactions of these factors and how they influence preterm birth.

Objectives. We compared the prevalence of risk factors for Black and White suicide decedents in Fulton County, Georgia, from 1988–2002. Methods. We used data from the Fulton County Medical Examiner’s Office to compile information on suicides that occurred in Fulton County between 1988 and 2002. We used the χ2 test and logistic regression to identify associations between suicide risk factors and race. Results. Black suicide decedents were more likely than White suicide decedents to be male (odds ratio [OR]=2.06; 95% confidence interval [CI]=1.38, 3.09), to be younger, (≤24 y [OR = 4.74; 95% CI = 2.88, 7.81]; 25–34 y [OR = 2.79; 95% CI = 1.74, 4.47]; 35–44 y [OR = 1.86; 95% CI = 1.13, 3.07]), and to hurt others in a suicide (OR = 4.22; 95% CI = 1.60, 11.15) but less likely to report depression (OR=0.63; 95% CI=0.48, 0.83), to have a family history of suicide (OR=0.08; 95% CI=0.01, 0.61), or to leave a suicide note (OR=0.37; 95% CI=0.26, 0.52). Conclusions. Future research should consider that Black suicide decedents are less likely to report depression than White suicide decedents. This suicide risk difference is important when developing effective suicide prevention programs.

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.

BACKGROUND Renal anomalies occur in about three infants per 1000 live births and have been associated with several environmental risk factors. Researchers have yet to assess the effect of maternal febrile illnesses on renal anomalies, even though febrile illnesses have been associated with other birth defects. Our objective was to determine whether maternal illness, fever, or medication use during the first trimester of pregnancy is associated with the occurrence of renal anomalies. METHODS In this population-based case-control study, we evaluated 192 infants with renal anomalies (renal agenesis [n = 44], obstructive defects [n = 134], and renal duplication defects [n = 14]) and 3029 infant without birth defects, all of whom were born in metropolitan Atlanta, Georgia, from 1968 through 1980. Maternal illness was defined as reported flu-like illness and/or episodic illness during the first trimester. RESULTS Our adjusted multivariate analyses showed that among the 192 case-infants, 38 had mothers with an illness (adjusted odds ratio [AOR], 1.71; 95% confidence interval [CI], 1.15–2.52), 20 had mothers who reported a fever (AOR, 1.80; 95% CI, 1.07–3.02) and 26 had mothers who reported taking medication (AOR, 1.69; 95% CI, 1.07–2.68). Fifteen mothers reported a fever and medication use (AOR, 1.90; 95% CI, 1.05–3.45). Nonprescription aspirin-containing medication use showed the strongest association (AOR, 3.45; 95% CI, 1.36–8.75) with renal anomalies. CONCLUSIONS Our data suggest that maternal exposure to illness, fever, and medication (particularly aspirin) may increase the risk of congenital renal anomalies. Birth Defects Research (Part A), 2003. © 2003 Wiley-Liss, Inc.

Vav and Vav2 are members of the Dbl family of proteins that act as guanine nucleotide exchange factors (GEFs) for Rho family proteins. Whereas Vav expression is restricted to cells of hematopoietic origin, Vav2 is widely expressed. Although Vav and Vav2 share highly related structural similarities and high sequence identity in their Dbl homology domains, it has been reported that they are active GEFs with distinct substrate specificities toward Rho family members. Whereas Vav displayed GEF activity for Rac1, Cdc42, RhoA, and RhoG, Vav2 was reported to exhibit GEF activity for RhoA, RhoB, and RhoG but not for Rac1 or Cdc42. Consistent with their distinct substrate targets, it was found that constitutively activated versions of Vav and Vav2 caused distinct transformed phenotypes when expressed in NIH 3T3 cells. In contrast to the previous findings, we found that Vav2 can act as a potent GEF for Cdc42, Rac1, and RhoA in vitro. Furthermore, we found that NH(2)-terminally truncated and activated Vav and Vav2 caused indistinguishable transforming actions in NIH 3T3 cells that required Cdc42, Rac1, and RhoA function. In addition, like Vav and Rac1, we found that Vav2 activated the Jun NH(2)-terminal kinase cascade and also caused the formation of lamellipodia and membrane ruffles in NIH 3T3 cells. Finally, Vav2-transformed NIH 3T3 cells showed up-regulated levels of Rac-GTP. We conclude that Vav2 and Vav share overlapping downstream targets and are activators of multiple Rho family proteins. Therefore, Vav2 may mediate the same cellular consequences in nonhematopoietic cells as Vav does in hematopoietic cells.

Publisher Summary This chapter discusses the analyses of transforming activity of Rho family activators. Members of the Rho family of small guanosine 5'-triphosphates (GTPases) are regulators of actin cytoskeletal organization, cell cycle progression, and activators of transcription factors that target growth-promoting or antiapoptotic genes. Rho family proteins have also been found to be essential for the transforming activity of other onco proteins. The chapter describes various assays that are useful in assessing the transforming functions of onco proteins that cause transformation—in part, by activating Rho family proteins. Two general applications of these assays are described. First, these assays can be used to implicate Rho family proteins in the transforming actions of oncoprotein. Second, these assays can also be used to delineate the structural and biochemical properties of a particular Rho activator that are important for promoting its transforming actions. The transformation assays described in the chapter can be used in conjunction with inhibitors of Rho protein activity to determine the requirement of specific Rho family members for transformation by different onco proteins. Transformation assays can also be helpful for determining the important structural and biochemical properties for the oncogenicity of certain proteins. The chapter also describes NIH 3T3 assays for the analyses of transformation caused by aberrant activation of Rho family proteins.

Activated forms of different Rho family members (CDC42, Rac1, RhoA, RhoB, and RhoG) have been shown to transform NIH 3T3 cells as well as contribute to Ras transformation. Rho family guanine nucleotide exchange factors (GEFs) (also known as Dbl family proteins) that activate CDC42, Rac1, and RhoA also demonstrate oncogenic potential. The faciogenital dysplasia gene product, FGD1, is a Dbl family member that has recently been shown to function as a CDC42-specific GEF. Mutations within the FGD1 locus cosegregate with faciogenital dysplasia, a multisystemic disorder resulting in extensive growth impairments throughout the skeletal and urogenital systems. Here we demonstrate that FGD1 expression is sufficient to cause tumorigenic transformation of NIH 3T3 fibroblasts. Although both FGD1 and constitutively activated CDC42 cooperated with Raf and showed synergistic focus-forming activity, both quantitative and qualitative differences in their functions were seen. FGD1 and CDC42 also activated common nuclear signaling pathways. However, whereas both showed comparable activation of c-Jun, CDC42 showed stronger activation of serum response factor and FGD1 was consistently a better activator of Elk-1. Although coexpression of FGD1 with specific inhibitors of CDC42 function demonstrated the dependence of FGD1 signaling activity on CDC42 function, FGD1 signaling activities were not always consistent with the direct or exclusive stimulation of CDC42 function. In summary, FGD1 and CDC42 signaling and transformation are distinct, thus suggesting that FGD1 may be mediating some of its biological activities through non-CDC42 targets.