Search

Constraints arise naturally in many scientific experiments/studies such as in, epidemiology, biology, toxicology, etc. and often researchers ignore such information when analyzing their data and use standard methods such as the analysis of variance (ANOVA). Such methods may not only result in a loss of power and efficiency in costs of experimentation but also may result poor interpretation of the data. In this paper we discuss constrained statistical inference in the context of linear mixed effects models that arise naturally in many applications, such as in repeated measurements designs, familial studies and others. We introduce a novel methodology that is broadly applicable for a variety of constraints on the parameters. Since in many applications sample sizes are small and/or the data are not necessarily normally distributed and furthermore error variances need not be homoscedastic (i.e. heterogeneity in the data) we use an empirical best linear unbiased predictor (EBLUP) type residual based bootstrap methodology for deriving critical values of the proposed test. Our simulation studies suggest that the proposed procedure maintains the desired nominal Type I error while competing well with other tests in terms of power. We illustrate the proposed methodology by re-analyzing a clinical trial data on blood mercury level. The methodology introduced in this paper can be easily extended to other settings such as nonlinear and generalized regression models. [ABSTRACT FROM AUTHOR]

Atherosclerosis, the leading death in the United State, is a disease in which a plaque builds up inside the arteries. As the plaque continues to grow, the shear force of the blood flow through the decreasing cross section of the lumen increases. This force may eventually cause rupture of the plaque, resulting in the formation of thrombus, and possibly heart attack. It has long been recognized that the formation of a plaque relates to the cholesterol concentration in the blood. For example, individuals with LDL above 190 mg/dL and HDL below 40 mg/dL are at high risk, while individuals with LDL below 100 mg/dL and HDL above 50 mg/dL are at no risk. In this paper, we developed a mathematical model of the formation of a plaque, which includes the following key variables: LDL and HDL, free radicals and oxidized LDL, MMP and TIMP, cytockines: MCP-1, IFN-γ, IL-12 and PDGF, and cells: macrophages, foam cells, T cells and smooth muscle cells. The model is given by a system of partial differential equations with in evolving plaque. Simulations of the model show how the combination of the concentrations of LDL and HDL in the blood determine whether a plaque will grow or disappear. More precisely, we create a map, showing the risk of plaque development for any pair of values (LDL,HDL). [ABSTRACT FROM AUTHOR]

Objectives: To extend existing research on the US health disadvantage relative to Europe by studying the relationships of disability with age from midlife to old age in the US and four European regions (England/Northern and Western Europe/Southern Europe/Eastern Europe) including their wealth-related differences, using a flexible statistical approach to model the age-functions. Methods: We used data from three studies on aging, with nationally representative samples of adults aged 50 to 85 from 15 countries (N = 48225): the US-American Health and Retirement Study (HRS), the English Longitudinal Study of Ageing (ELSA) and the Survey of Health, Ageing and Retirement in Europe (SHARE). Outcomes were mobility limitations and limitations in instrumental activities of daily living. We applied fractional polynomials of age to determine best fitting functional forms for age on disability in each region, while controlling for socio-demographic characteristics and important risk factors (hypertension, diabetes, obesity, smoking, physical inactivity). Results: Findings showed high levels of disability in the US with small age-related changes between 50 and 85. Levels of disability were generally lower in Eastern Europe, followed by England and Southern Europe and lowest in Northern and Western Europe. In these latter countries age-related increases of disability, though, were steeper than in the US, especially in Eastern and Southern Europe. For all countries and at all ages, disability levels were higher among adults with low wealth compared to those with high wealth, with largest wealth-related differences among those in early old age in the USA. Conclusions: This paper illustrates considerable variations of disability and its relationship with age. It supports the hypothesis that less developed social policies and more pronounced socioeconomic inequalities are related to higher levels of disability and an earlier onset of disability. [ABSTRACT FROM AUTHOR]

The objectives of this paper are to predict life years lost associated with obesity-related diseases (ORDs) for U.S. non-smoking adults, and to examine the relationship between those ORDs and mortality. Data from the National Health Interview Survey, 1997–2000, were used. We employed mixed proportional hazard models to estimate the association between those ORDs and mortality and used simulations to project life years lost associated with the ORDs. We found that obesity-attributable comorbidities are associated with large decreases in life years and increases in mortality rates. The life years lost associated with ORDs is more marked for younger adults than older adults, for blacks than whites, for males than females, and for the more obese than the less obese. Using U.S. non-smoking adults aged 40 to 49 years as an example to illustrate percentage of the life years lost associated with ORDs, we found that the mean life years lost associated with ORDs for U.S. non-smoking black males aged 40 to 49 years with a body mass index above 40 kg/m2 was 5.43 years, which translates to a 7.5% reduction in total life years. White males of the same age range and same degree of obesity lost 5.23 life years on average – a 6.8% reduction in total life years, followed by black females (5.04 years, a 6.5% reduction in life years), and white females (4.7 years, a 5.8% reduction in life years). Overall, ORDs increased chances of dying and lessened life years by 0.2 to 11.7 years depending on gender, race, BMI classification, and age. [ABSTRACT FROM AUTHOR]

We conduct a detailed investigation of correlations between real-time expressions of individuals made across the United States and a wide range of emotional, geographic, demographic, and health characteristics. We do so by combining (1) a massive, geo-tagged data set comprising over 80 million words generated in 2011 on the social network service Twitter and (2) annually-surveyed characteristics of all 50 states and close to 400 urban populations. Among many results, we generate taxonomies of states and cities based on their similarities in word use; estimate the happiness levels of states and cities; correlate highly-resolved demographic characteristics with happiness levels; and connect word choice and message length with urban characteristics such as education levels and obesity rates. Our results show how social media may potentially be used to estimate real-time levels and changes in population-scale measures such as obesity rates. [ABSTRACT FROM AUTHOR]

Background: Environmental nontuberculous mycobacteria (NTM) are ubiquitous organisms with which humans commonly interact. The epidemiologic characteristics of NTM diseases including mortality rate and its associated factors remain largely unknown. In this study, we explored the geographical area of exposure and mortality and comorbid conditions of affected persons to determine environment, host, and host-pathogen interactive factors. Methods: We analyzed mortality related to nontuberculous mycobacterial infections from 1999 through 2010 by examining multiple-cause-of-death data from the National Center for Health Statistics. Among those who died with these diseases, we analyzed age-adjusted mortality rates, trends, associations with demographic variables, and comorbid conditions and correlated this information with similar data for tuberculosis-related mortality during the same time. Measurements and Mean Results: From 1999 through 2010, nontuberculous mycobacterial disease was reported as an immediate cause of death in 2,990 people in the United States with a combined overall mean age-adjusted mortality rate of 0.1 per 100,000 person-years. A significant increase in the number of NTM related deaths was seen from 1999 through 2010 (R2 = 0.72, p<0.0001), but it was not significant after adjustment for age. Persons aged 55 years and older, women, those living in Hawaii and Louisiana, and those of non-Hispanic, white ethnicity had higher mortality rates. Compared to tuberculosis-related mortality, chronic obstructive pulmonary disease, bronchiectasis, HIV, interstitial lung diseases, and tobacco use were significantly more common in persons with nontuberculous mycobacteria-related deaths. Conclusions: Nontuberculous mycobacteria-related death numbers are rising and are unevenly distributed. The strong association of nontuberculous mycobacterial disease with age suggests that its prevalence will increase as the United States population ages. [ABSTRACT FROM AUTHOR]

Understanding mechanisms fostering coexistence between invasive and resident species is important in predicting ecological, economic, or health impacts of invasive species. The non-native mosquitoes Aedes aegypti and Culex quinquefasciatus have been resident in the southeastern United States for over a century. They coexist at some urban sites with the more recent invasive Aedes albopictus, which is usually superior in interspecific competition. We tested predictions of temporal and spatial habitat segregation that foster coexistence of these resident species with the superior invasive competitor. We measured spatial and temporal patterns of site occupancy and abundance for all three species among standard oviposition traps in metropolitan Tampa, Florida. Consistent with the condition-specific competition hypothesis, A. albopictus and A. aegypti abundances were greater and C. quinquefasciatus abundance was lower late (September) versus early (June) in the rainy season, and the proportional increase of A. albopictus abundance was greater than that of A. aegypti. These results are postulated to result from greater dry-season egg mortality and associated greater rainy-season competitive superiority of larvae of A. albopictus, followed by A. aegypti, and C. quinquefasciatus. Spatial partitioning among landscape variables was also evident among species, with A. albopictus more likely to oviposit across a range of open grass landscapes whereas A. aegypti were mostly restricted to cemeteries. Culex quinquefasciatus showed a shift in abundance from cemeteries early in the rainy season to developed areas characterized by built environments with large proportions of impervious surfaces late in the rainy season, where A. albopictus was not in its highest abundance. These results suggest that both temporal and spatial variation, and their interaction, may contribute to local coexistence between Aedes and Culex mosquito species in urban areas. [ABSTRACT FROM AUTHOR]

Freshwater turtles may ingest baited fish hooks because many are opportunistic scavengers. Although the ingestion of fish hooks is known to be a source of mortality in multiple vertebrate groups, the prevalence of hook ingestion by freshwater turtles has not been well studied. We trapped turtles from five rivers in the southeastern United States and used radiographs to examine over 600 individuals of four species. Depending on the species, sex, and age class, 0–33% of turtles contained ingested fish hooks. For some species, larger turtles were more likely to contain a fish hook than smaller individuals. Freshwater turtle demography suggests that even small increases in adult mortality may lead to population declines. If our study areas are representative of other aquatic systems that receive fishing pressure, this work likely identifies a potential conflict between a widespread, common recreational activity (i.e., fishing) and an imperiled taxonomic group. [ABSTRACT FROM AUTHOR]

Purpose: Non-CML myeloproliferative neoplasms (MPN) include essential thrombocythemia (ET), polycythemia vera (PV), and myelofibrosis (MF). Reported median overall survival (OS) ranges from a few to several years for MF, a decade or more for ET and PV. The study objective was to compare US survival rates of ET, PV, and MF patients with matched non-MPN/non-cancer controls in a nationally representative database. Patients and Methods: Data were taken retrospectively from the Survey, Epidemiology, and End Results (SEER)-Medicare linked database. Medicare enrollees with a new SEER MPN diagnosis between Jan 1, 2001 and Dec 31, 2007 were eligible. First MPN diagnosis was required at or after Medicare enrollment to allow for continuous follow-up. Non-MPN/non-cancer control groups were selected from Medicare separately for each MPN subtype and demographically matched to cases at a ratio of 5∶1. Survival was determined starting from the case diagnosis date using the Kaplan-Meier method. Results: A total of 3,364 MPN patients (n = 1,217 ET; 1,625 PV; 522 MF) met the inclusion criteria and were matched to controls. Mean age was 78.4, 76.1, and 77.4 years for ET, PV, and MF, respectively, and percent female was 63, 50, and 41. Median OS was significantly (p<0.05) lower for MPN cases vs. controls (ET: 68 vs. 101 months; PV: 65 vs. 104; MF: 24 vs. 106). Conclusions: In the US Medicare population, survival in MF patients was worse than that of patients with ET or PV and significantly worse than matched controls. Survival of patients with ET or PV was substantially inferior to matched controls. These findings have implications for the clinical management of MPN patients and underscore the need for effective therapies in all MPN subtypes. [ABSTRACT FROM AUTHOR]

Background: Physical inactivity, ambient air pollution and obesity are modifiable risk factors for non-communicable diseases, with the first accounting for 10% of premature deaths worldwide. Although community level interventions may target each simultaneously, research on the relationship between these risk factors is lacking. Objectives: After comparing spatial interpolation methods to determine the best predictor for particulate matter (PM2.5; PM10) and ozone (O3) exposures throughout the U.S., we evaluated the cross-sectional association of ambient air pollution with leisure-time physical inactivity among adults. Methods: In this cross-sectional study, we assessed leisure-time physical inactivity using individual self-reported survey data from the Centers for Disease Control and Prevention's 2011 Behavioral Risk Factor Surveillance System. These data were combined with county-level U.S. Environmental Protection Agency air pollution exposure estimates using two interpolation methods (Inverse Distance Weighting and Empirical Bayesian Kriging). Finally, we evaluated whether those exposed to higher levels of air pollution were less active by performing logistic regression, adjusting for demographic and behavioral risk factors, and after stratifying by body weight category. Results: With Empirical Bayesian Kriging air pollution values, we estimated a statistically significant 16–35% relative increase in the odds of leisure-time physical inactivity per exposure class increase of PM2.5 in the fully adjusted model across the normal weight respondents (p-value<0.0001). Evidence suggested a relationship between the increasing dose of PM2.5 exposure and the increasing odds of physical inactivity. Conclusions: In a nationally representative, cross-sectional sample, increased community level air pollution is associated with reduced leisure-time physical activity particularly among the normal weight. Although our design precludes a causal inference, these results provide additional evidence that air pollution should be investigated as an environmental determinant of inactivity. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate cardiovascular and psychiatric morbidity in patient visits with obstructive sleep apnea (OSA) with insomnia (OSA+Insomnia) versus OSA without insomnia (OSA-Insomnia) in a nationally representative US sample. Methods: A retrospective case-control study of epidemiologic databases (National Ambulatory Medical Care Survey and National Hospital Ambulatory Medical Care Survey) representing an estimated ± standard error (SE) 62,253,910±5,274,747 (unweighted count = 7234) patient visits with diagnosis of OSA from 1995–2010, was conducted. An estimated 3,994,104±791,386 (unweighted count = 658) were classified as OSA+Insomnia and an estimated 58,259,806±4,849,800 (unweighted count = 6576) as OSA-Insomnia. Logistic regression analysis was carried out using OSA+Insomnia versus OSA-Insomnia as the dependent variable, and age (>50 years versus ≤50 years), sex, race (‘White’ versus ‘non-White’), essential hypertension, heart failure, ischemic heart disease, cardiac dysrhythmia, cerebrovascular disease, diabetes, obesity, hyperlipidemia, depressive, anxiety, and adjustment disorders (includes PTSD), hypersomnia and all medications used as independent variables. All comorbidities were physician diagnosed using the ICD9-CM. Results: Among patient visits with OSA, an estimated 6.4%±0.9% also had insomnia. Logistic regression analysis revealed that the OSA+Insomnia group was significantly more likely to have essential hypertension (all ICD9-CM codes 401) (OR = 1.83, 95% CI 1.27–2.65) and provisionally more likely to have cerebrovascular disease (ICD9-CM codes 430–438) (OR = 6.58, 95% CI 1.66–26.08). The significant OR for cerebrovascular disease was considered provisional because the unweighted count was <30. Conclusions: In a nationally representative sample, OSA+Insomnia was associated significantly more frequently with essential hypertension than OSA-Insomnia, a finding that has not been previously reported. In contrast to studies that have considered patient self-reports of psychological morbidity, the absence of a significant association with psychiatric disorders in our study may be indicative of the fact that we considered only physician-rated psychiatric syndromes meeting ICD9-CM criteria. Our findings among the OSA+Insomnia group are therefore most likely conservative. [ABSTRACT FROM AUTHOR]

Childhood family structure has been shown to play an important role in shaping a child's life course development, especially in industrialised societies. One hypothesis which could explain such findings is that parental investment is likely to be diluted in families without both natural parents. Most empirical studies have examined the influence of only one type of family disruption or composition (e.g. father absence) making it difficult to simultaneously compare the effects of different kinds of family structure on children's future outcomes. Here we use a large, rich data source (n = 16,207) collected by Alfred Kinsey and colleagues in the United States from 1938 to 1963, to examine the effects of particular childhood family compositions and compare between them. The dataset further allows us to look at the effects of family structure on an array of traits relating to sexual maturity, reproduction, and risk-taking. Our results show that, for both sexes, living with a single mother or mother and stepfather during childhood was often associated with faster progression to life history events and greater propensity for risk-taking behaviours. However, living with a single father or father and stepmother was typically not significantly different to having both natural parents for these outcomes. Our results withstand adjustment for socioeconomic status, age, ethnicity, age at puberty (where applicable), and sibling configuration. While these results support the hypothesis that early family environment influences subsequent reproductive strategy, the different responses to the presence or absence of different parental figures in the household rearing environment suggests that particular family constructions exert independent influences on childhood outcomes. Our results suggest that father-absent households (i.e. single mothers or mothers and stepfathers) are most highly associated with subsequent fast life history progressions, compared with mother-absent households, and those with two natural parents. [ABSTRACT FROM AUTHOR]

Background: The role of surgical care in promoting global health is the subject of much debate. The Global Burden of Disease 2010 study (GBD 2010) offers a new opportunity to consider where surgery fits amongst global health priorities. The GBD 2010 reinforces the DALY as the preferred methodology for determining the relative contribution of disease categories to overall global burden of disease without reference to the likelihood of each category requiring surgery. As such, we hypothesize that the GBD framework underestimates the role of surgery in addressing the global burden of disease. Methods and Findings: We compiled International Classification of Diseases, Version 9, codes from the United States Nationwide Inpatient Sample from 2010. Using the primary diagnosis code for each hospital admission, we aggregated admissions into GBD 2010 disease sub-categories. We queried each hospitalization for a major operation to determine the frequency of admitted patients whose care required surgery. Major operation was defined according to the Agency for Healthcare Research and Quality (AHRQ). In 2010, 10 million major inpatient operations were performed in the United States, associated with 28.6% of all admissions. Major operations were performed in every GBD disease subcategory (range 0.2%–84.0%). The highest frequencies of operation were in the subcategories of Musculoskeletal (84.0%), Neoplasm (61.4%), and Transport Injuries (43.2%). There was no disease subcategory that always required an operation; nor was there any disease subcategory that never required an operation. Conclusions: Surgical care cuts across the entire spectrum of GBD disease categories, challenging dichotomous traditional classifications of ‘surgical’ versus ‘nonsurgical’ diseases. Current methods of measuring global burden of disease do not reflect the fundamental role operative intervention plays in the delivery of healthcare services. Novel methodologies should be aimed at understanding the integration of surgical services into health systems to address the global burden of disease. [ABSTRACT FROM AUTHOR]

Ovarian cancer is the most lethal gynecological disease affecting women in the US. The Cancer Genome Atlas Network identified p53 mutations in 96% of high-grade serous ovarian carcinomas, demonstrating its critical role. Additionally, the Transforming Growth Factor Beta (TGFβ) pathway is dysfunctional in various malignancies, including ovarian cancer. This study investigated how expression of wild-type, mutant, or the absence of p53 alters ovarian cancer cell response to TGFβ signaling, as well as the response of the ovarian surface epithelium and the fallopian tube epithelium to TGFβ. Only ovarian cancer cells expressing wild-type p53 were growth inhibited by TGFβ, while ovarian cancer cells that were mutant or null p53 were not. TGFβ induced migration in p53 null SKOV3 cells, which was not observed in SKOV3 cells with stable expression of mutant p53 R273H. Knockdown of wild-type p53 in the OVCA 420 ovarian cancer cells enhanced cell migration in response to TGFβ. Increased protein expression of DKK1 and TMEPAI, two pro-invasive genes with enhanced expression in late stage metastatic ovarian cancer, was observed in p53 knockdown and null cells, while cells stably expressing mutant p53 demonstrated lower DKK1 and TMEPAI induction. Expression of mutant p53 or loss of p53 permit continued proliferation of ovarian cancer cell lines in the presence of TGFβ; however, cells expressing mutant p53 exhibit reduced migration and decreased protein levels of DKK1 and TMEPAI. [ABSTRACT FROM AUTHOR]

Objective: The 75% of older adults with multiple chronic conditions are at risk of therapeutic competition (i.e. treatment for one condition may adversely affect a coexisting condition). The objective was to determine the prevalence of potential therapeutic competition in community-living older adults. Methods: Cross-sectional descriptive study of a representative sample of 5,815 community-living adults 65 and older in the U.S, enrolled 2007–2009. The 14 most common chronic conditions treated with at least one medication were ascertained from Medicare claims. Medication classes recommended in national disease guidelines for these conditions and used by ≥2% of participants were identified from in-person interviews conducted 2008–2010. Criteria for potential therapeutic competition included: 1), well-acknowledged adverse medication effect; 2) mention in disease guidelines; or 3) report in a systematic review or two studies published since 2000. Outcomes included prevalence of situations of potential therapeutic competition and frequency of use of the medication in individuals with and without the competing condition. Results: Of 27 medication classes, 15 (55.5%) recommended for one study condition may adversely affect other study conditions. Among 91 possible pairs of study chronic conditions, 25 (27.5%) have at least one potential therapeutic competition. Among participants, 1,313 (22.6%) received at least one medication that may worsen a coexisting condition; 753 (13%) had multiple pairs of such competing conditions. For example, among 846 participants with hypertension and COPD, 16.2% used a nonselective beta-blocker. In only 6 of 37 cases (16.2%) of potential therapeutic competition were those with the competing condition less likely to receive the medication than those without the competing condition. Conclusions: One fifth of older Americans receive medications that may adversely affect coexisting conditions. Determining clinical outcomes in these situations is a research and clinical priority. Effects on coexisting conditions should be considered when prescribing medications. [ABSTRACT FROM AUTHOR]

Background: Cryptococcus gattii is a fungal pathogen causing an emerging outbreak in the United States Pacific Northwest (PNW). Treatment guidelines for cryptococcosis are primarily based on data from C. neoformans infections; applicability to PNW C. gattii infection is unknown. We evaluated the relationship between initial antifungal treatment and outcomes for PNW C.gattii patients. Methods: Cases were defined as culture-confirmed invasive C. gattii infections among residents of Oregon and Washington States during 2004–2011. Clinical data were abstracted from medical records through one year of follow-up. Recommended initial treatment for central nervous system (CNS), bloodstream, and severe pulmonary infections is amphotericin B and 5-flucytosine; for non-severe pulmonary infections, recommended initial treatment is fluconazole. Alternative initial treatment was defined as any other initial antifungal treatment. Results: Seventy patients survived to diagnosis; 50 (71%) received the recommended initial treatment and 20 (29%) received an alternative. Fewer patients with pulmonary infections [21 (64%)] than CNS infections [25 (83%)] received the recommended initial treatment (p = 0.07). Among patients with pulmonary infections, those with severe infections received the recommended initial treatment less often than those with non-severe infections (11% vs. 83%, p<0.0001). Eight patients with severe pulmonary infections received alternative initial treatments; three died. Four patients with non-severe pulmonary infections received alternative initial treatments; two died. There was a trend towards increased three-month mortality among patients receiving alternative vs. recommended initial treatment (30% vs. 14%, p = 0.12), driven primarily by increased mortality among patients with pulmonary disease receiving alternative vs. recommended initial treatment (42% vs. 10%, p = 0.07). Conclusions: C.gattii patients with pulmonary infections – especially severe infections – may be less likely to receive recommended treatment than those with CNS infections; alternative treatment may be associated with increased mortality. Reasons for receipt of alternative treatment among C.gattii patients in this area should be investigated, and clinician awareness of recommended treatment reinforced. [ABSTRACT FROM AUTHOR]

Background: Approximately one-third of patients with multiple sclerosis (MS) are unresponsive to, or intolerant of, interferon (IFN) therapy, prompting a switch to other disease-modifying therapies. Clinical outcomes of switching therapy are unknown. This retrospective study assessed differences in relapse rates among patients with MS switching from IFN to fingolimod or glatiramer acetate (GA) in a real-world setting. Methods: US administrative claims data from the PharMetrics Plus™ database were used to identify patients with MS who switched from IFN to fingolimod or GA between October 1, 2010 and March 31, 2012. Patients were matched 1∶1 using propensity scores within strata (number of pre-index relapses) on demographic (e.g. age and gender) and disease (e.g. timing of pre-index relapse, comorbidities and symptoms) characteristics. A claims-based algorithm was used to identify relapses while patients were persistent with therapy over 360 days post-switch. Differences in both the probability of experiencing a relapse and the annualized relapse rate (ARR) while persistent with therapy were assessed. Results: The matched sample population contained 264 patients (n = 132 in each cohort). Before switching, 33.3% of patients in both cohorts had experienced at least one relapse. During the post-index persistence period, the proportion of patients with at least one relapse was lower in the fingolimod cohort (12.9%) than in the GA cohort (25.0%), and ARRs were lower with fingolimod (0.19) than with GA (0.51). Patients treated with fingolimod had a 59% lower probability of relapse (odds ratio, 0.41; 95% confidence interval [CI], 0.21–0.80; p = 0.0091) and 62% fewer relapses per year (rate ratio, 0.38; 95% CI, 0.21–0.68; p = 0.0013) compared with those treated with GA. Conclusions: In a real-world setting, patients with MS who switched from IFNs to fingolimod were significantly less likely to experience relapses than those who switched to GA. [ABSTRACT FROM AUTHOR]

Background and Hypothesis: Even within accepted normal ranges, higher serum phosphorus, dietary phosphorus density, parathyroid hormone (PTH) and alkaline phosphatase (ALP) are independent predictors of cardiovascular mortality. Lower serum 25-hydroxy vitamin D (25(OH)D) also predicts adverse cardiovascular outcomes. We hypothesized that vascular dysfunction accompanying subtle disturbances of these bone metabolism parameters would result in associations with increased low grade albuminuria. Study Population and Measures: We examined participants in the National Health and Nutrition Examination Surveys 1999–2010 (N = 19,383) with estimated glomerular filtration rate (eGFR) ≥60 ml/min/1.73 m2 and without severe albuminuria (urine albumin:creatinine ratio (ACR) <300 mg/g). Albuminuria was quantified as ACR and fractional albumin excretion (FEalb). Results: Increasing quintiles of dietary phosphorus density, serum phosphorus and ALP were not associated with higher ACR or FEalb. The lowest versus highest quintile of 25(OH)D was associated with greater albuminuria, but not after adjustment for other covariates including cardiovascular risk factors. An association between the highest versus lowest quintile of bone-specific ALP and greater ACR persisted after covariate adjustment, but was not accompanied by an independent association with FEalb. Increasing quintiles of PTH demonstrated associations with both higher ACR and FEalb that were not abolished by adjusting for covariates including age, gender, race, body mass index, diabetes, blood pressure, history of cardiovascular disease, smoking, eGFR, 25(OH)D, season of measurement, lipids, hemoglobin and C-reactive protein. Adjusted increases in ACR and FEalb associated with the highest versus lowest quintile of PTH were 19% (95% confidence interval 7–28% p<0.001) and 17% (8–31% p = 0.001) respectively. Conclusion: In this population, of the bone mineral parameters associated with cardiovascular outcomes, only PTH is independently associated with ACR and FEalb. [ABSTRACT FROM AUTHOR]

Background: American Black men who have sex with men (MSM) are disproportionately affected by HIV, but the factors associated with this concentrated epidemic are not fully understood. Methods: Black MSM were enrolled in 6 US cities to evaluate a multi-component prevention intervention, with the current analysis focusing on the correlates of being newly diagnosed with HIV compared to being HIV-uninfected or previously diagnosed with HIV. Results: HPTN 061 enrolled 1553 Black MSM whose median age was 40; 30% self-identified exclusively as gay or homosexual, 29% exclusively as bisexual, and 3% as transgender. About 1/6th (16.2%) were previously diagnosed with HIV (PD); of 1263 participants without a prior HIV diagnosis 7.6% were newly diagnosed (ND). Compared to PD, ND Black MSM were younger (p<0.001); less likely to be living with a primary partner (p<0.001); more likely to be diagnosed with syphilis (p<0.001), rectal gonorrhea (p = 0.011) or chlamydia (p = 0.020). Compared to HIV-uninfected Black MSM, ND were more likely to report unprotected receptive anal intercourse (URAI) with a male partner in the last 6 months (p<0.001); and to be diagnosed with syphilis (p<0.001), rectal gonorrhea (p = 0.004), and urethral (p = 0.025) or rectal chlamydia (p<0.001). They were less likely to report female (p = 0.002) or transgender partners (p = 0.018). Multivariate logistic regression analyses found that ND Black MSM were significantly more likely than HIV-uninfected peers to be unemployed; have STIs, and engage in URAI. Almost half the men in each group were poor, had depressive symptoms, and expressed internalized homophobia. Conclusions: ND HIV-infected Black MSM were more likely to be unemployed, have bacterial STIs and engage in URAI than other Black MSM. Culturally-tailored programs that address economic disenfranchisement, increase engagement in care, screen for STIs, in conjunction with safer sex prevention interventions, may help to decrease further transmission in this heavily affected community. [ABSTRACT FROM AUTHOR]

Objectives: To estimate the number of men who have sex with men and women who are HIV-positive in the United States, and to compare HIV prevalence rates between men who have sex with men and women, men who have sex with men only, and men who have sex with women exclusively. Methods: Following PRISMA guidelines, we conducted a systematic review and meta-analysis of reports referencing HIV prevalence and men who have sex with men and women. We searched PubMed and Ovid PsycINFO for peer-reviewed, U.S.-based articles reporting on HIV prevalence among men who have sex with men and women. We conducted event rate, effect size, moderation and sensitivity analyses. Results: We estimate that 1.0% of U.S. males are bisexually-behaving, and that 121,800 bisexually-behaving men are HIV-positive. Men who have sex with men and women are less than half as likely to be HIV-positive as men who have sex with men only (16.9% vs. 33.3%; OR = 0.41, 95% CI: 0.31, 0.54), but more than five times as likely to be HIV-positive as men who have sex with women exclusively (18.3% vs. 3.5%; OR = 5.71, 95% CI: 3.47, 9.39). They are less likely to engage in unprotected receptive anal intercourse than men who have sex with men only (15.9% vs. 35.0%; OR = 0.36, 95% CI: 0.28, 0.46). Men who have sex with men and women in samples with high racial/ethnic minority proportions had significantly higher HIV prevalence than their counterparts in low racial/ethnic minority samples. Conclusions: This represents the first meta-analysis of HIV prevalence in the U.S. between men who have sex with men and women and men who have sex with men only. Data collection, research, and HIV prevention and care delivery specifically tailored to men who have sex with men and women are necessary to better quantify and ameliorate this population’s HIV burden. [ABSTRACT FROM AUTHOR]

Background: Evaluating environmental health risks in communities requires models characterizing geographic and demographic patterns of exposure to multiple stressors. These exposure models can be constructed from multivariable regression analyses using individual-level predictors (microdata), but these microdata are not typically available with sufficient geographic resolution for community risk analyses given privacy concerns. Methods: We developed synthetic geographically-resolved microdata for a low-income community (New Bedford, Massachusetts) facing multiple environmental stressors. We first applied probabilistic reweighting using simulated annealing to data from the 2006–2010 American Community Survey, combining 9,135 microdata samples from the New Bedford area with census tract-level constraints for individual and household characteristics. We then evaluated the synthetic microdata using goodness-of-fit tests and by examining spatial patterns of microdata fields not used as constraints. As a demonstration, we developed a multivariable regression model predicting smoking behavior as a function of individual-level microdata fields using New Bedford-specific data from the 2006–2010 Behavioral Risk Factor Surveillance System, linking this model with the synthetic microdata to predict demographic and geographic smoking patterns in New Bedford. Results: Our simulation produced microdata representing all 94,944 individuals living in New Bedford in 2006–2010. Variables in the synthetic population matched the constraints well at the census tract level (e.g., ancestry, gender, age, education, household income) and reproduced the census-derived spatial patterns of non-constraint microdata. Smoking in New Bedford was significantly associated with numerous demographic variables found in the microdata, with estimated tract-level smoking rates varying from 20% (95% CI: 17%, 22%) to 37% (95% CI: 30%, 45%). Conclusions: We used simulation methods to create geographically-resolved individual-level microdata that can be used in community-wide exposure and risk assessment studies. This approach provides insights regarding community-scale exposure and vulnerability patterns, valuable in settings where policy can be informed by characterization of multi-stressor exposures and health risks at high resolution. [ABSTRACT FROM AUTHOR]

We developed linguistics-driven prediction models to estimate the risk of suicide. These models were generated from unstructured clinical notes taken from a national sample of U.S. Veterans Administration (VA) medical records. We created three matched cohorts: veterans who committed suicide, veterans who used mental health services and did not commit suicide, and veterans who did not use mental health services and did not commit suicide during the observation period (n = 70 in each group). From the clinical notes, we generated datasets of single keywords and multi-word phrases, and constructed prediction models using a machine-learning algorithm based on a genetic programming framework. The resulting inference accuracy was consistently 65% or more. Our data therefore suggests that computerized text analytics can be applied to unstructured medical records to estimate the risk of suicide. The resulting system could allow clinicians to potentially screen seemingly healthy patients at the primary care level, and to continuously evaluate the suicide risk among psychiatric patients. [ABSTRACT FROM AUTHOR]

Background: Ovarian cancer is the most lethal gynecologic disease in the United States, with more women dying from this cancer than all gynecological cancers combined. Ovarian cancer has been termed the “silent killer” because some patients do not show clear symptoms at an early stage. Currently, there is a lack of approved and effective early diagnostic tools for ovarian cancer. There is also an apparent severe knowledge gap of ovarian cancer in general and of its indicative symptoms among both public and many health professionals. These factors have significantly contributed to the late stage diagnosis of most ovarian cancer patients (63% are diagnosed at Stage III or above), where the 5-year survival rate is less than 30%. The paucity of knowledge concerning ovarian cancer in the United States is unknown. Methods: The present investigation examined current public awareness and knowledge about ovarian cancer. The study implemented design strategies to develop an unbiased survey with quality control measures, including the modern application of multiple statistical analyses. The survey assessed a reasonable proxy of the US population by crowdsourcing participants through the online task marketplace Amazon Mechanical Turk, at a highly condensed rate of cost and time compared to traditional recruitment methods. Conclusion: Knowledge of ovarian cancer was compared to that of breast cancer using repeated measures, bias control and other quality control measures in the survey design. Analyses included multinomial logistic regression and categorical data analysis procedures such as correspondence analysis, among other statistics. We confirmed the relatively poor public knowledge of ovarian cancer among the US population. The simple, yet novel design should set an example for designing surveys to obtain quality data via Amazon Mechanical Turk with the associated analyses. [ABSTRACT FROM AUTHOR]

Background: Dyslipidemia, typically recognized as high serum triglyceride, high low-density lipoprotein cholesterol (LDL-C) or low high-density lipoprotein cholesterol (HDL-C) levels, are associated with nonalcoholic fatty liver disease (NAFLD). However, low LDL-C levels could result from defects in lipoprotein metabolism or impaired liver synthetic function, and may serve as ab initio markers for unrecognized liver diseases. Whether such relationships exist in the general population has not been investigated. We hypothesized that despite common conception that low LDL-C is desirable, it might be associated with elevated liver enzymes due to metabolic liver diseases. Methods and Findings: We examined the associations between alanine aminotransferase (ALT), aspartate aminotransferase (AST) and major components of serum lipid profiles in a nationally representative sample of 23,073 individuals, who had no chronic viral hepatitis and were not taking lipid-lowering medications, from the National Health and Nutrition Examination Survey (NHANES) from 1999 to 2010. ALT and AST exhibited non-linear U-shaped associations with LDL-C and HDL-C, but not with triglyceride. After adjusting for potential confounders, individuals with LDL-C less than 40 and 41–70 mg/dL were associated with 4.2 (95% CI 1.5–11.7, p = 0.007) and 1.6 (95% CI 1.1–2.5, p = 0.03) times higher odds of abnormal liver enzymes respectively, when compared with those with LDL-C values 71–100 mg/dL (reference group). Surprisingly, those with HDL-C levels above 100 mg/dL was associated with 3.2 (95% CI 2.1–5.0, p<0.001) times higher odds of abnormal liver enzymes, compared with HDL-C values of 61–80 mg/dL. Conclusions: Both low LDL-C and high HDL-C, often viewed as desirable, were associated with significantly higher odds of elevated transaminases in the general U.S. adult population. Our findings underscore an underestimated biological link between lipoprotein metabolism and liver diseases, and raise a potential need for liver evaluation among over 10 million people with particularly low LDL-C or high HDL-C in the United States. [ABSTRACT FROM AUTHOR]

Biomarkers of selenium are necessary for assessing selenium status in humans, since soil variation hinders estimation of selenium intake from foods. In this study, we measured the concentration of plasma selenium, selenoprotein P (SEPP1), and glutathione peroxidase (GPX3) activity and their interindividual differences in 383 low-income blacks and whites selected from a stratified random sample of adults aged 40–79 years, who were participating in a long-term cohort study in the southeastern United States (US). We assessed the utility of these biomarkers to determine differences in selenium status and their association with demographic, socio-economic, dietary, and other indicators. Dietary selenium intake was assessed using a validated food frequency questionnaire designed for the cohort, matched with region-specific food selenium content, and compared with the US Recommended Dietary Allowances (RDA) set at 55 µg/day. We found that SEPP1, a sensitive biomarker of selenium nutritional status, was significantly lower among blacks than whites (mean 4.4±1.1 vs. 4.7±1.0 mg/L, p = 0.006), with blacks less than half as likely to have highest vs. lowest quartile SEPP1 concentration (Odds Ratio (OR) 0.4, 95% Confidence Interval (CI) 0.2–0.8). The trend in a similar direction was observed for plasma selenium among blacks and whites, (mean 115±15.1 vs. 118±17.7 µg/L, p = 0.08), while GPX3 activity did not differ between blacks and whites (136±33.3 vs. 132±33.5 U/L, p = 0.320). Levels of the three biomarkers were not correlated with estimated dietary selenium intake, except for SEPP1 among 10% of participants with the lowest selenium intake (≤57 µg/day). The findings suggest that SEPP1 may be an effective biomarker of selenium status and disease risk in adults and that low selenium status may disproportionately affect black and white cohort participants. [ABSTRACT FROM AUTHOR]

Anemia is one of the many complications of chronic kidney disease (CKD). However, the current prevalence of anemia in CKD patients in the United States is not known. Data from the National Health and Nutrition Examination Survey (NHANES) in 2007–2008 and 2009–2010 were used to determine the prevalence of anemia in subjects with CKD. The analysis was limited to adults aged >18 who participated in both the interview and exam components of the survey. Three outcomes were assessed: the prevalence of CKD, the prevalence of anemia in subjects with CKD, and the self-reported treatment of anemia. CKD was classified into 5 stages based on the glomerular filtration rate and evidence of kidney damage, in accordance with the guidelines of the National Kidney Foundation. Anemia was defined as serum hemoglobin levels ≤12 g/dL in women and ≤13 g/dL in men. We found that an estimated 14.0% of the US adult population had CKD in 2007–2010. Anemia was twice as prevalent in people with CKD (15.4%) as in the general population (7.6%). The prevalence of anemia increased with stage of CKD, from 8.4% at stage 1 to 53.4% at stage 5. A total of 22.8% of CKD patients with anemia reported being treated for anemia within the previous 3 months–14.6% of patients at CKD stages 1–2 and 26.4% of patients at stages 3–4. These results update our knowledge of the prevalence and treatment of anemia in CKD in the United States. [ABSTRACT FROM AUTHOR]

Traumatic brain injury (TBI) is an important public health problem, comparable to stroke in incidence and prevalence. Few interventions have proven efficacy in TBI, and clinical trials are, therefore, necessary to advance management in TBI. We describe the current clinical trial landscape in traumatic brain injury and compare it with the trial efforts for stroke. For this, we analysed all stroke and TBI studies registered on the US Clinical Trials (www.clinicaltrials.gov) database over a 10-year period (01/01/2000 to 01/31/2013). This methodology has been previously used to analyse clinical trial efforts in other specialties. We describe the research profile in each area: total number of studies, total number of participants and change in number of research studies over time. We also analysed key study characteristics, such as enrolment number and scope of recruitment. We found a mismatch between relative public health burden and relative research effort in each disease. Despite TBI having comparable prevalence and higher incidence than stroke, it has around one fifth of the number of clinical trials and participant recruitment. Both stroke and TBI have experienced an increase in the number of studies over the examined time period, but the rate of growth for TBI is one third that for stroke. Small-scale (<1000 participants per trial) and single centre studies form the majority of clinical trials in both stroke and TBI, with TBI having significantly fewer studies with international recruitment. We discuss the consequences of these findings and how the situation might be improved. A sustained research effort, entailing increased international collaboration and rethinking the methodology of running clinical trials, is required in order to improve outcomes after traumatic brain injury. [ABSTRACT FROM AUTHOR]

Objective: Studies examining the relation of information processing speed, as measured by reaction time, with mortality are scarce. We explored these associations in a representative sample of the US population. Methods: Participants were 5,134 adults (2,342 men) aged 20–59 years from the Third National Health and Nutrition Examination Survey (NHANES III, 1988–94). Results: Adjusted for age, sex, and ethnic minority status, a 1 SD slower reaction time was associated with a raised risk of mortality from all-causes (HR = 1.25, 95% CI 1.12, 1.39) and cardiovascular disease (CVD) (HR = 1.36, 95% CI 1.17, 1.58). Having 1 SD more variable reaction time was also associated with greater risk of all-cause (HR = 1.36, 95% CI 1.19, 1.55) and CVD (HR = 1.50, 95% CI 1.33, 1.70) mortality. No associations were observed for cancer mortality. The magnitude of the relationships was comparable in size to established risk factors in this dataset, such as smoking. Interpretation: Alongside better-established risk factors, reaction time is associated with increased risk of premature death and cardiovascular disease. It is a candidate risk factor for all-cause and cause-specific mortality. [ABSTRACT FROM AUTHOR]

Objectives: In February 2012, the Advisory Committee on Immunization Practices (ACIP) advised that all adults aged ≥65 years receive a single dose of reduced-antigen-content tetanus, diphtheria, and acellular pertussis (Tdap), expanding on a 2010 recommendation for adults >65 that was limited to those with close contact with infants. We evaluated clinical and economic outcomes of adding Tdap booster of adults aged ≥65 to “baseline” practice [full-strength DTaP administered from 2 months to 4–6 years, and one dose of Tdap at 11–64 years replacing decennial Td booster], using a dynamic model. Methods: We constructed a population-level disease transmission model to evaluate the cost-effectiveness of supplementing baseline practice by vaccinating 10% of eligible adults aged ≥65 with Tdap replacing the decennial Td booster. US population effects, including indirect benefits accrued by unvaccinated persons, were estimated during a 1-year period after disease incidence reached a new steady state, with consequences of deaths and long-term pertussis sequelae projected over remaining lifetimes. Model outputs include: cases by severity, encephalopathy, deaths, costs (of vaccination and pertussis care) and quality-adjusted life-years (QALYs) associated with each strategy. Results in terms of incremental cost/QALY gained are presented from payer and societal perspectives. Sensitivity analyses vary key parameters within plausible ranges. Results: For the US population, the intervention is expected to prevent >97,000 cases (>4,000 severe and >5,000 among infants) of pertussis annually at steady state. Additional vaccination costs are $4.7 million. Net cost savings, including vaccination costs, are $47.7 million (societal perspective) and $44.8 million (payer perspective). From both perspectives, the intervention strategy is dominant (less costly, and more effective by >3,000 QALYs) versus baseline. Results are robust to sensitivity analyses and alternative scenarios. Conclusions: Immunization of eligible adults aged ≥65, consistent with the current ACIP recommendation, is cost saving from both payer and societal perspectives. [ABSTRACT FROM AUTHOR]

Background: A limiting antigen avidity enzyme immunoassay (HIV-1 LAg-Avidity assay) was recently developed for cross-sectional HIV incidence estimation. We evaluated the performance of the LAg-Avidity assay alone and in multi-assay algorithms (MAAs) that included other biomarkers. Methods and Findings: Performance of testing algorithms was evaluated using 2,282 samples from individuals in the United States collected 1 month to >8 years after HIV seroconversion. The capacity of selected testing algorithms to accurately estimate incidence was evaluated in three longitudinal cohorts. When used in a single-assay format, the LAg-Avidity assay classified some individuals infected >5 years as assay positive and failed to provide reliable incidence estimates in cohorts that included individuals with long-term infections. We evaluated >500,000 testing algorithms, that included the LAg-Avidity assay alone and MAAs with other biomarkers (BED capture immunoassay [BED-CEIA], BioRad-Avidity assay, HIV viral load, CD4 cell count), varying the assays and assay cutoffs. We identified an optimized 2-assay MAA that included the LAg-Avidity and BioRad-Avidity assays, and an optimized 4-assay MAA that included those assays, as well as HIV viral load and CD4 cell count. The two optimized MAAs classified all 845 samples from individuals infected >5 years as MAA negative and estimated incidence within a year of sample collection. These two MAAs produced incidence estimates that were consistent with those from longitudinal follow-up of cohorts. A comparison of the laboratory assay costs of the MAAs was also performed, and we found that the costs associated with the optimal two assay MAA were substantially less than with the four assay MAA. Conclusions: The LAg-Avidity assay did not perform well in a single-assay format, regardless of the assay cutoff. MAAs that include the LAg-Avidity and BioRad-Avidity assays, with or without viral load and CD4 cell count, provide accurate incidence estimates. [ABSTRACT FROM AUTHOR]

The broad diversity in physicians’ judgments on controversial health care topics may reflect differences in religious characteristics, political ideologies, and moral intuitions. We tested an existing measure of moral intuitions in a new population (U.S. physicians) to assess its validity and to determine whether physicians’ moral intuitions correlate with their views on controversial health care topics as well as other known predictors of these intuitions such as political affiliation and religiosity. In 2009, we mailed an 8-page questionnaire to a random sample of 2000 practicing U.S. physicians from all specialties. The survey included the Moral Foundations Questionnaire (MFQ30), along with questions on physicians’ judgments about controversial health care topics including abortion and euthanasia (no moral objection, some moral objection, strong moral objection). A total of 1032 of 1895 (54%) physicians responded. Physicians’ overall mean moral foundations scores were 3.5 for harm, 3.3 for fairness, 2.8 for loyalty, 3.2 for authority, and 2.7 for sanctity on a 0–5 scale. Increasing levels of religious service attendance, having a more conservative political ideology, and higher sanctity scores remained the greatest positive predictors of respondents objecting to abortion (β = 0.12, 0.23, 0.14, respectively, each p<0.001) as well as euthanasia (β = 0.08, 0.17, and 0.17, respectively, each p<0.001), even after adjusting for demographics. Higher authority scores were also significantly negatively associated with objection to abortion (β = −0.12, p<0.01), but not euthanasia. These data suggest that the relative importance physicians place on the different categories of moral intuitions may predict differences in physicians’ judgments about morally controversial topics and may interrelate with ideology and religiosity. Further examination of the diversity in physicians’ moral intuitions may prove illustrative in describing and addressing moral differences that arise in medical practice. [ABSTRACT FROM AUTHOR]

Background: Pseudobulbar affect (PBA) is a neurological condition characterized by involuntary, sudden, and frequent episodes of laughing and/or crying, which can be socially disabling. Although PBA occurs secondary to many neurological conditions, with an estimated United States (US) prevalence of up to 2 million persons, it is thought to be under-recognized and undertreated. The PBA Registry Series (PRISM) was established to provide additional PBA symptom prevalence data in a large, representative US sample of patients with neurological conditions known to be associated with PBA. Methods: Participating clinicians were asked to enroll ≥20 consenting patients with any of 6 conditions: Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), Parkinson’s disease (PD), stroke, or traumatic brain injury (TBI). Patients (or their caregivers) completed the Center for Neurologic Study−Lability Scale (CNS-LS) and an 11-point scale measuring impact of the neurological condition on the patient’s quality of life (QOL). Presence of PBA symptoms was defined as a CNS−LS score ≥13. Demographic data and current use of antidepressant or antipsychotic medications were also recorded. Results: PRISM enrolled 5290 patients. More than one third of patients (n = 1944; 36.7%) had a CNS-LS score ≥13, suggesting PBA symptoms. The mean (SD) score measuring impact of neurological condition on QOL was significantly higher (worse) in patients with CNS-LS ≥13 vs <13 (6.7 [2.5] vs. 4.7 [3.1], respectively; P<0.0001 two-sample t-test). A greater percentage of patients with CNS−LS ≥13 versus <13 were using antidepressant/antipsychotic medications (53.0% vs 35.4%, respectively; P<0.0001, chi-square test). Conclusions: Data from PRISM, the largest clinic-based study to assess PBA symptom prevalence, showed that PBA symptoms were common among patients with diverse neurological conditions. Higher CNS−LS scores were associated with impaired QOL and greater use of antipsychotic/antidepressant medications. These data underscore a need for greater awareness, recognition, and diagnosis of PBA. [ABSTRACT FROM AUTHOR]

Background: Coal is produced across 25 states and provides 42% of US energy. With production expected to increase 7.6% by 2035, proximate populations remain at risk of exposure to carcinogenic coal products such as silica dust and organic compounds. It is unclear if population exposure is associated with increased risk, or even which cancers have been studied in this regard. Methods: We performed a systematic review of English-language manuscripts published since 1980 to determine if coal mining exposure was associated with increased cancer risk (incidence and mortality). Results: Of 34 studies identified, 27 studied coal mining as an occupational exposure (coal miner cohort or as a retrospective risk factor) but only seven explored health effects in surrounding populations. Overall, risk assessments were reported for 20 cancer site categories, but their results and frequency varied considerably. Incidence and mortality risk assessments were: negative (no increase) for 12 sites; positive for 1 site; and discordant for 7 sites (e.g. lung, gastric). However, 10 sites had only a single study reporting incidence risk (4 sites had none), and 11 sites had only a single study reporting mortality risk (2 sites had none). The ecological study data were particularly meager, reporting assessments for only 9 sites. While mortality assessments were reported for each, 6 had only a single report and only 2 sites had reported incidence assessments. Conclusions: The reported assessments are too meager, and at times contradictory, to make definitive conclusions about population cancer risk due to coal mining. However, the preponderance of this and other data support many of Hill’s criteria for causation. The paucity of data regarding population exposure and risk, the widespread geographical extent of coal mining activity, and the continuing importance of coal for US energy, warrant further studies of population exposure and risk. [ABSTRACT FROM AUTHOR]

Background: HPV4 is approved as a series of three timed doses expected to result in efficacy against specific HPV infections. Completion rates in the US are quite low at the same time the structure of health care delivery is changing. The aim of this study was to determine how the patient-, clinic- and systems-level characteristics facilitate or hinder the timely completion of three HPV4 doses in both adolescent and adult female populations in a high-risk safety net population. Methods: This is a retrospective study in which patient-, clinic- and systems-level data are abstracted from the electronic medical record (EMR) for all females 10–26 years of age receiving at least one dose of HPV4 between July 1, 2006 and October 1, 2009. Results: Adults were more likely to complete the three dose series if they had at least one health care visit in addition to their HPV4 visit, (aOR = 1.54 (95% CI:1.10, 2.15). Adults were less likely to complete the three dose series if they received their second HPV4 dose at an acute health care, preventive care or postpartum visits compared to an HPV4-only visit (aOR = 0.31 (95% CI: 0.13, 0.72), 0.12 (0.04, 0.35), 0.30 (0.14, 0.62), respectively). Hispanic adults were less likely than whites to complete the series (aOR = 0.24 (95% CI:0.10, 0.59). 39% of adolescents who completed two doses completed the series. Conclusions: HPV4 is more likely to be effectively administered to adults in a safety net population if multiple health care needs can be met within the health care system. [ABSTRACT FROM AUTHOR]

While there is a large body of evidence that poor subjective sleep quality is related to lower subjective well-being, studies on the relation of objective sleep measures and subjective well-being are fewer in number and less consistent in their findings. Using data of the Survey of Mid-Life in the United States (MIDUS), we investigated whether duration and quality of sleep, assessed by actigraphy, were related to subjective well-being and whether this relationship was mediated by subjective sleep quality. Three hundred and thirteen mainly white American individuals from the general population and 128 urban-dwelling African American individuals between 35 and 85 years of age were studied cross-sectionally. Sleep duration, variability of sleep duration, sleep onset latency, and time awake after sleep onset were assessed by actigraphy over a period of 7 days. Subjective sleep quality was assessed with the Pittsburgh Sleep Quality Index, positive psychological well-being and symptoms of psychological distress were assessed with the Satisfaction with Life Scale and the Mood and Anxiety Symptom Questionnaire. In both white and African Americans high day-to-day variability in sleep duration was related to lower levels of subjective well-being controlling age, gender, educational and marital status, and BMI. By contrast, sleep duration, sleep onset latency, and time awake after sleep onset were not related to subjective well-being controlling covariates and other sleep variables. Moreover, the relationship between variability in sleep duration and well-being was partially mediated by subjective sleep quality. The findings show that great day-to-day variability in sleep duration – more than average sleep duration – is related to poor subjective sleep quality and poor subjective well-being. [ABSTRACT FROM AUTHOR]

Objectives: This study builds upon current studies of atrial fibrillation (AF) and health outcomes by examining more comprehensively the humanistic burden of illness (quality of life, activity impairment, and healthcare resource utilization) among adult patients with AF, using a large, nationally representative sample and matched controls. Methods: Data were analyzed from the Internet-based 2009 US National Health and Wellness Survey. Outcomes were Mental and Physical Component Summary (MCS and PCS) and health utility scores from the SF-12, activity impairment, hospitalizations, and healthcare provider and emergency room (ER) visits. Patients with self-reported diagnosis of AF were matched randomly on age and gender with an equal number of respondents without AF. Generalized linear models examined outcomes as a function of AF vs. non-AF status, controlling for CHADS2 score, comorbidity counts, demographics, and clinical variables. Exploratory structural equation modeling assessed the above in an integrated model of humanistic burden. Results: Mean age of AF patients (1,296 from a total sample of 75,000) was 64.9 years and 65.1% were male. Adjusting for covariates, compared with non-AF patients, AF patients had lower MCS, PCS, and utility scores, greater activity impairment (rate ratio = 1.26), more traditional provider visits (rate ratio = 1.43), and increased odds of ER visits (OR = 2.53) and hospitalizations (OR = 2.71). Exploratory structural equation modeling analyses revealed that persons with AF experienced a significantly higher overall humanistic burden. Conclusions: This study highlights and clarifies the substantial burden of AF and its implications for preparing efficacious AF management plans to address the imminent rise in prevalence. [ABSTRACT FROM AUTHOR]

Objective: Our aim was to examine the relative contributions of changes in dietary fat intake and use of cholesterol-lowering medications to changes in concentrations of total cholesterol among adults in the United States from 1988–1994 to 2007–2008. Method: We used data from adults aged 20–74 years who participated in National Health and Nutrition Examination Surveys from 1988–1994 to 2007–2008. The effect of change in dietary fat intake on concentrations of total cholesterol was estimated by the use of equations developed by Keys, Hegsted, and successors. Results: Age-adjusted mean concentrations of total cholesterol were 5.60 mmol/L (216 mg/dl) during 1988–1994 falling to 5.09 mmol/L (197 mg/dl) in 2007–2008 (P<0.001). No significant changes in the intake of total fat, saturated fat, polyunsaturated fat, and dietary cholesterol were observed from 1988–1994 to 2007–2008. However, the age-adjusted use of cholesterol-lowering medications increased from 1.6% to 12.5% (P<0.001). The various equations suggested that changes in dietary fat made minimal contributions to the observed trend in mean concentrations of total cholesterol. The increased use of cholesterol-lowering medications was estimated to account for approximately 46% of the change. Discussion: Mean concentrations of total cholesterol among adults in the United States have declined by ∼4% since 1988–1994. The increased use of cholesterol-lowering medications has apparently accounted for about half of this small fall. Further substantial decreases in cholesterol might be potentially achievable by implementing effective and feasible public health interventions to promote the consumption of a more healthful diet by US adults. Disclaimer: The findings and conclusions in this article are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention. [ABSTRACT FROM AUTHOR]

Objectives: We examined temporal trends, spatial variation, and gender differences in rates of hospitalization due to acute myocardial infarction. Methods: We used data from the Centers for Disease Control National Environmental Public Health Tracking Network to evaluate temporal trends, geographic variation, and gender differences in 20 Environmental Public Health Tracking Network states from 2000 to 2008. A longitudinal linear mixed effects model was fitted to the acute myocardial infarction hospitalization rates for the states and counties within each state to examine the overall temporal trend. Results: There was a significant overall decrease in age-adjusted acute myocardial infarction hospitalization rates between 2000 and 2008, with most states showing over a 20% decline during the period. The ratio of male/female rates for acute myocardial infarction hospitalization rates remained relatively consistent over time, approximately two-fold higher in men compared to women. A large geographic variability was found for age-adjusted acute myocardial infarction hospitalization rates, with the highest rates found in the Northeastern states. Results of two ecological analyses revealed that the NE region remained significantly associated with increased AMI hospitalization rates after adjustment for socio-demographic factors. Conclusions: This investigation is one of the first to explore geographic differences in AMI age adjusted hospital rates in individuals 35+ years of age for 2000–2008. We showed a decreasing trend in AMI hospitalization rates in men and women. A large geographic variability in rates was found with particularly higher rates in the New England/Mid-Atlantic region of the US and lower rates in the mountain and Pacific states of the tracking network. It appeared that over time this disparity in rates became less notable. [ABSTRACT FROM AUTHOR]

It is generally believed that the infant's microbiota is established during the first 1–2 years of life. However, there is scarce data on its characterization and its comparison to the adult-like microbiota in consecutive years. Aim: To characterize and compare the intestinal microbiota in healthy young children (1–4 years) and healthy adults from the North Carolina region in the U.S. using high-throughput bacterial phylogenetic microarray analysis. Methods: Detailed characterization and comparison of the intestinal microbiota of healthy children aged 1–4 years old (n = 28) and healthy adults of 21–60 years (n = 23) was carried out using the Human Intestinal Tract Chip (HITChip) phylogenetic microarray targeting the V1 and V6 regions of 16S rRNA and quantitative PCR. Results: The HITChip microarray data indicate that Actinobacteria, Bacilli, Clostridium cluster IV and Bacteroidetes are the predominant phylum-like groups that exhibit differences between young children and adults. The phylum-like group Clostridium cluster XIVa was equally predominant in young children and adults and is thus considered to be established at an early age. The genus-like level show significant 3.6 fold (higher or lower) differences in the abundance of 26 genera between young children and adults. Young U.S. children have a significantly 3.5-fold higher abundance of Bifidobacterium species than the adults from the same location. However, the microbiota of young children is less diverse than that of adults. Conclusions: We show that the establishment of an adult-like intestinal microbiota occurs at a later age than previously reported. Characterizing the microbiota and its development in the early years of life may help identify ‘windows of opportunity’ for interventional strategies that may promote health and prevent or mitigate disease processes. [ABSTRACT FROM AUTHOR]

Background: In April 2009, the most recent pandemic of influenza A began. We present the first estimates of pandemic mortality based on the newly-released final data on deaths in 2009 and 2010 in the United States. Methods: We obtained data on influenza and pneumonia deaths from the National Center for Health Statistics (NCHS). Age- and sex-specific death rates, and age-standardized death rates, were calculated. Using negative binomial Serfling-type methods, excess mortality was calculated separately by sex and age groups. Results: In many age groups, observed pneumonia and influenza cause-specific mortality rates in October and November 2009 broke month-specific records since 1959 when the current series of detailed US mortality data began. Compared to the typical pattern of seasonal flu deaths, the 2009 pandemic age-specific mortality, as well as influenza-attributable (excess) mortality, skewed much younger. We estimate 2,634 excess pneumonia and influenza deaths in 2009–10; the excess death rate in 2009 was 0.79 per 100,000. Conclusions: Pandemic influenza mortality skews younger than seasonal influenza. This can be explained by a protective effect due to antigenic cycling. When older cohorts have been previously exposed to a similar antigen, immune memory results in lower death rates at older ages. Age-targeted vaccination of younger people should be considered in future pandemics. [ABSTRACT FROM AUTHOR]

Chronic hepatitis C virus (HCV) infection can lead to advanced liver disease (AdvLD), including cirrhosis, decompensated cirrhosis, and liver cancer. The aim of this study was to determine recent historical rates of HCV patient progression to AdvLD and to project AdvLD prevalence through 2015. We first determined total 2008 US chronic HCV prevalence from the National Health and Nutrition Evaluation Surveys. Next, we examined disease progression and associated non-pharmacological costs of diagnosed chronic HCV-infected patients between 2007–2009 in the IMS LifeLink and CMS Medicare claims databases. A projection model was developed to estimate AdvLD population growth through 2015 in patients diagnosed and undiagnosed as of 2008, using the 2007–2009 progression rates to generate a “worst case” projection of the HCV-related AdvLD population (i.e., scenario where HCV treatment is the same in the forecasted period as it was before 2009). We found that the total diagnosed chronic HCV population grew from 983,000 to 1.19 million in 2007–2009, with patients born from 1945–1964 accounting for 75.0% of all patients, 83.7% of AdvLD patients, and 79.2% of costs in 2009, indicating that HCV is primarily a disease of the “baby boomer” population. Non-pharmacological costs grew from $7.22 billion to $8.63 billion, with the majority of growth derived from the 60,000 new patients that developed AdvLD in 2007–2009, 91.5% of whom were born between 1945 and 1964. The projection model estimated the total AdvLD population would grow from 195,000 in 2008 to 601,000 in 2015, with 73.5% of new AdvLD cases from patients undiagnosed as of 2008. AdvLD prevalence in patients diagnosed as of 2008 was projected to grow 6.5% annually to 303,000 patients in 2015. These findings suggest that strategies to diagnose and treat HCV-infected patients are urgently needed to increase the likelihood that progression is interrupted, particularly for patients born from 1945–1964. [ABSTRACT FROM AUTHOR]

Much uncertainty remains about the origin and public health implications of livestock-associated methicillin-resistant Staphylococcus aureus (LA-MRSA). This study aimed to investigate the occurrence and prevalence of MRSA in general and LA-MRSA in particular in pigs and farm workers in five states. We collected nasal swabs from pigs and farm workers at 45 swine herds (21 antibiotic-free herds; 24 conventional herds) in Illinois, Iowa, Minnesota, North Carolina and Ohio. MRSA was isolated from 50 of 1085 pigs (4.6%) and 31 of 148 (20.9%) of farm workers. MRSA-positive pigs and people were clustered in four conventional swine farms in Iowa and Illinois. Based on genotyping, spa type t034, a common livestock associated variant, was predominant among both human and swine isolates. These results confirm the presence of LA-MRSA in pigs and swine farm workers in the USA, but the prevalence found is relatively low compared with European studies. [ABSTRACT FROM AUTHOR]

Objective: To assess the association between TV viewing and obesity by race/ethnicity and socio-economic status. Design: Cross-sectional analysis of 5,087 respondents to the Health Information National Trends Survey (HINTS), a nationally representative sample of US adults. Multivariate regression models were computed to assess the association between quartiles of TV viewing and BMI, stratified by race/ethnicity, educational attainment, employment and health insurance status. Results: Findings indicate that increased TV viewing was associated with higher odds for being overweight/obese in the entire sample, while adjusting for physical activity and other confounders. After stratification by race/ethnicity, increased odds for overweight/obesity in the 3rd and 4th quartiles of TV viewing (e.g., 3rd quartile- cumulative OR = 1.43, 95%CI 1.07–1.92) was observed in non-Hispanic whites, with statistical significance. In non-Hispanic blacks and Hispanics, the odds were similar to whites, but did not reach statistical significance. Significant relations between greater TV viewing and increased BMI were observed in college graduates and non-graduates, those with health insurance and the employed. Conclusions: This study extends previous research by examining potential inconsistencies in this association between various racial/ethnic groups and some socio-economic variables, which primarily were not found. [ABSTRACT FROM AUTHOR]

Obesity in children has become an epidemic in the U.S. and is particularly prominent in minority populations such as Mexican-Americans. In addition to physical activity and diet, genetics also plays a role in obesity etiology. A few studies in adults and adolescents suggest a link between obesity and paraoxonase 1 (PON1), a multifunctional enzyme that can metabolize organophosphate pesticides and also has antioxidant properties. We determined PON1192 genotype and arylesterase levels (ARYase, measure of PON1 enzyme quantity), to characterize the relationship between PON1 and obesity in young Mexican-American children (n = 373) living in an agricultural community in California. Since PON1 polymorphisms and obesity both vary between ethnic groups, we estimated proportional genetic ancestry using 106 ancestral informative markers (AIMs). Among children, PON1192 allele frequencies were 0.5 for both alleles, and the prevalence of obesity was high (15% and 33% at ages two and five, respectively). The average proportion of European, African, and Native American ancestry was 0.40, 0.09, and 0.51, yet there was wide inter-individual variation. We found a significantly higher odds of obesity (9.3 and 2.5- fold) in PON1192QQ children compared to PON1192RR children at ages two and five, respectively. Similar relationships were seen with BMI Z-scores at age two and waist circumference at age five. After adjusting for genetic ancestry in models of PON1 and BMI Z-score, effect estimates for PON1192 genotype changed 15% and 9% among two and five year old children, respectively, providing evidence of genetic confounding by population stratification. However even after adjustment for genetic ancestry, the trend of increased BMI Z-scores with increased number of PON1192 Q alleles remained. Our findings suggest that PON1 may play a role in obesity independent of genetic ancestry and that studies of PON1 and health outcomes, especially in admixed populations, should account for differences due to population stratification. [ABSTRACT FROM AUTHOR]

Introduction: Leishmaniasis is an important public health problem in the Americas. A Cochrane review published in 2009 analyzed 38 randomized controlled trials (RCT). We conducted a systematic review to evaluate the effects of therapeutic interventions for American cutaneous and mucocutaneous leishmaniasis. Methods: All studies were extracted from PubMed, Embase, Lilacs (2009 to July, 2012 respectively), the Cochrane Central Register of Controlled Trials (6-2012) and references of identified publications. RCTs’ risk of bias was assessed. Results: We identified 1865 references of interest; we finally included 10 new RCTs. The risk of bias scored low or unclear for most domains. Miltefosine was not significantly different from meglumine antimoniate in the complete cure rate at 6 months (4 RCT; 584 participants; ITT; RR: 1.12; 95%CI: 0.85 to 1.47; I2 78%). However a significant difference in the rate of complete cure favoring miltefosine at 6 months was found in L. panamensis and L. guyanensis (2 RCTs, 206 participants; ITT; RR: 1.22; 95%CI: 1.02 to 1.46; I2 0%). One RCT found that meglumine antimoniate was superior to pentamidine in the rate of complete cure for L. braziliensis (80 participants, ITT; RR: 2.21; 95%CI: 1.41 to 3.49), while another RCT assessing L. guyanensis did not find any significant difference. Although meta-analysis of three studies found a significant difference in the rate of complete cure at 3 months favoring imiquimod versus placebo (134 participants; ITT; RR: 1.45; 95%CI: 1.12 to 1.88; I2 0%), no significant differences were found at 6 and 12 months. Thermotherapy and nitric oxide were not superior to meglumine antimoniate. Conclusion: Therapeutic interventions for American cutaneous and mucocutaneous leishmaniasis are varied and should be decided according to the context. Since mucosal disease is the more neglected form of leishmaniasis a multicentric trial should be urgently considered. [ABSTRACT FROM AUTHOR]

Background: The increasing incidence and heterogeneous behavior of intestinal neuroendocrine tumors (iNETs) pose a clinicopathological challenge. Our goal was to decribe the prognostic value of the new WHO 2010 grading and the AJCC/UICC TNM staging systems for iNETs. Moreover, outcomes of patients treated with somatostatin analogs were assessed. Methods: We collected epidemiological and clinicopathological data from 93 patients with histologically proven iNETs including progression and survival outcomes. The WHO 2010 grading and the AJCC/UICC TNM staging systems were applied for all cases. RECIST criteria were used to define progression. Kaplan-Meier analyses for progression free survival (PFS) and overall survival (OS) were performed. Results: Mean follow-up was 58.6 months (4–213 months). WHO 2010 grading yielded PFS and disease-specific OS of 125.0 and 165.8 months for grade 1 (G1), 100.0 and 144.2 months for G2 and 15.0 and 15.8 months for G3 tumors (p = 0.004 and p = 0.001). Using AJCC staging, patients with stage I and II tumors had no progression and no deaths. Stage III and IV patients demonstrated PFS of 138.4 and 84.7 months (p = 0.003) and disease-specific OS of 210.0 and 112.8 months (p = 0.017). AJCC staging also provided informative PFS (91.2 vs. 50.0 months, p = 0.004) and OS (112.3 vs. 80.0 months, p = 0.005) measures with somatostatin analog use in stage IV patients. Conclusion: Our findings underscore the complementarity of WHO 2010 and AJCC classifications in providing better estimates of iNETS disease outcomes and extend the evidence for somatostatin analog benefit in patients with metastatic disease. [ABSTRACT FROM AUTHOR]

Background: Factors that increase the risk of central line-associated bloodstream infections (CLABSIs) are not fully understood. Recently, Hospital Compare began compiling data from hospital-required reporting to the CDC's National Healthcare Safety Network on CLABSIs in intensive care units (ICUs), at over 4,000 Medicare-certified hospitals in the United States, and made this data accessible on a central website. Also available on the same website are results from the Hospital Consumer Assessment of Healthcare Providers and Systems survey of patients' hospital experiences. Utilizing both databases, our objective was to determine whether patients' hospital experiences were significantly associated with increased risk for reported ICU CLABSI. Methods and Findings: We conducted a zero-inflated Poisson regression analysis at the hospital level on CLABSI-observed cases by ICUs in acute care hospitals (n = 1987) in the United States between January 1, 2011, and December 31, 2011. During this period there were a total of 10,866 CLABSI cases and 9,543,765 central line days. In our final model, the percent of patients who reported that they “sometimes” or “never” received help as soon as they wanted was significantly associated with an increased risk for CLABSIs. Conclusions: Using national datasets, we found that inpatients' hospital experiences were significantly associated with an increased risk of ICU reported CLABSIs. This study suggests that hospitals with lower staff responsiveness, perhaps because of an understaffing of nurse and supportive personnel, are at an increased risk for CLABSIs. This study bolsters the evidence that patient surveys may be a useful surrogate to predicting the incidence of hospital acquired conditions, including CLABSIs. Moreover, our study found that poor staff responsiveness may be indicative of greater hospital problems and generally poorly performing hospitals; and that this finding may be a symptom of hospitals with a multitude of problems, including patient safety problems, and not a direct cause. [ABSTRACT FROM AUTHOR]

Background: COPD is characterized by variability in exercise capacity and physical activity (PA), and acute exacerbations (AEs). Little is known about the relationship between daily step count, a direct measure of PA, and the risk of AEs, including hospitalizations. Methods: In an observational cohort study of 169 persons with COPD, we directly assessed PA with the StepWatch Activity Monitor, an ankle-worn accelerometer that measures daily step count. We also assessed exercise capacity with the 6-minute walk test (6MWT) and patient-reported PA with the St. George's Respiratory Questionnaire Activity Score (SGRQ-AS). AEs and COPD-related hospitalizations were assessed and validated prospectively over a median of 16 months. Results: Mean daily step count was 5804±3141 steps. Over 209 person-years of observation, there were 263 AEs (incidence rate 1.3±1.6 per person-year) and 116 COPD-related hospitalizations (incidence rate 0.56±1.09 per person-year). Adjusting for FEV1 % predicted and prednisone use for AE in previous year, for each 1000 fewer steps per day walked at baseline, there was an increased rate of AEs (rate ratio 1.07; 95%CI = 1.003–1.15) and COPD-related hospitalizations (rate ratio 1.24; 95%CI = 1.08–1.42). There was a significant linear trend of decreasing daily step count by quartiles and increasing rate ratios for AEs (P = 0.008) and COPD-related hospitalizations (P = 0.003). Each 30-meter decrease in 6MWT distance was associated with an increased rate ratio of 1.07 (95%CI = 1.01–1.14) for AEs and 1.18 (95%CI = 1.07–1.30) for COPD-related hospitalizations. Worsening of SGRQ-AS by 4 points was associated with an increased rate ratio of 1.05 (95%CI = 1.01–1.09) for AEs and 1.10 (95%CI = 1.02–1.17) for COPD-related hospitalizations. Conclusions: Lower daily step count, lower 6MWT distance, and worse SGRQ-AS predict future AEs and COPD–related hospitalizations, independent of pulmonary function and previous AE history. These results support the importance of assessing PA in patients with COPD, and provide the rationale to promote PA as part of exacerbation-prevention strategies. [ABSTRACT FROM AUTHOR]

Background: A striking characteristic of the past four influenza pandemic outbreaks in the United States has been the multiple waves of infections. However, the mechanisms responsible for the multiple waves of influenza or other acute infectious diseases are uncertain. Understanding these mechanisms could provide knowledge for health authorities to develop and implement prevention and control strategies. Materials and Methods: We exhibit five distinct mechanisms, each of which can generate two waves of infections for an acute infectious disease. The first two mechanisms capture changes in virus transmissibility and behavioral changes. The third mechanism involves population heterogeneity (e.g., demography, geography), where each wave spreads through one sub-population. The fourth mechanism is virus mutation which causes delayed susceptibility of individuals. The fifth mechanism is waning immunity. Each mechanism is incorporated into separate mathematical models, and outbreaks are then simulated. We use the models to examine the effects of the initial number of infected individuals (e.g., border control at the beginning of the outbreak) and the timing of and amount of available vaccinations. Results: Four models, individually or in any combination, reproduce the two waves of the 2009 H1N1 pandemic in the United States, both qualitatively and quantitatively. One model reproduces the two waves only qualitatively. All models indicate that significantly reducing or delaying the initial numbers of infected individuals would have little impact on the attack rate. Instead, this reduction or delay results in a single wave as opposed to two waves. Furthermore, four of these models also indicate that a vaccination program started earlier than October 2009 (when the H1N1 vaccine was initially distributed) could have eliminated the second wave of infection, while more vaccine available starting in October would not have eliminated the second wave. [ABSTRACT FROM AUTHOR]

Background: Colorectal cancer (CRC) metastasis is a leading cause of cancer-related deaths in the United States. The molecular mechanisms underlying this complex, multi-step pathway are yet to be completely elucidated. Recent reports have stressed the importance of intra-tumoral heterogeneity in the development of a metastatic phenotype. The purpose of this study was to characterize the intra-tumoral phenotypic heterogeneity between two iso-clonal human colon cancer sublines HCT116 and HCT116b on their ability to undergo metastatic colonization and survive under growth factor deprivation stress (GFDS). Materials and Methods: HCT116 and HCT116b cells were transfected with green fluorescence protein and subcutaneously injected into BALB/c nude male mice. Once xenografts were established, they were excised and orthotopically implanted into other male BALB/c nude mice using microsurgical techniques. Animal tissues were studied for metastases using histochemical techniques. Microarray analysis was performed to generate gene signatures associated with each subline. In vitro assessment of growth factor signaling pathway was performed under GFDS for 3 and 5 days. Results: Both HCT116 and HCT116b iso-clonal variants demonstrated 100% primary tumor growth, invasion and peritoneal spread. However, HCT116 was highly metastatic with 68% metastasis observed in liver and/or lungs compared to 4% in HCT116b. Microarray analysis revealed an upregulation of survival and metastatic genes in HCT116 cells compared to HCT116b cells. In vitro analysis showed that HCT116 upregulated survival and migratory signaling proteins and downregulated apoptotic agents under GFDS. However, HCT116b cells effectively showed the opposite response under stress inducing cell death. Conclusions: We demonstrate the importance of clonal variation in determining metastatic potential of colorectal cancer cells using the HCT116/HCT116b iso-clonal variants in an orthotopic metastatic mouse model. Determination of clonal heterogeneity in patient tumors can serve as useful tools to identify clinically relevant biomarkers for diagnostic and therapeutic assessment of metastatic colorectal cancer. [ABSTRACT FROM AUTHOR]