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Find video protocols related to scientific articles indexed in Pubmed.
Shed Syndecan-1 Translocates to the Nucleus of Cells Delivering Growth Factors and Inhibiting Histone Acetylation: A Novel Mechanism of Tumor-Host Crosstalk.
J. Biol. Chem.
PUBLISHED: 11-19-2014
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The heparan sulfate proteoglycan syndecan-1 is proteolytically shed from the surface of multiple myeloma cells and is abundant in the bone marrow microenvironment where it promotes tumor growth, angiogenesis, and metastasis. In the present study, we demonstrate for the first time that shed syndecan-1 present in the medium conditioned by tumor cells is taken up by bone marrow-derived stromal cells and transported to the nucleus. Translocation of shed syndecan-1 (sSDC1) to the nucleus was blocked by addition of exogenous heparin or heparan sulfate, pretreatment of conditioned medium with heparinase III or growth of cells in sodium chlorate, indicating that sulfated heparan sulfate chains are required for nuclear translocation. Interestingly, cargo bound to sSDC1 heparan sulfate chains (i.e. hepatocyte growth factor (HGF)) was transported to the nucleus along with sSDC1 and removal of heparan sulfate-bound cargo from sSDC1 abolished its translocation to the nucleus. Once in the nucleus, sSDC1 binds to the histone acetyltransferase (HAT) enzyme p300 and HAT activity and histone acetylation are diminished. These findings reveal a novel function for shed syndecan-1 in mediating tumor-host crosstalk by shuttling growth factors to the nucleus and by altering histone acetylation in host cells. In addition, this work has broad implications beyond myeloma because shed syndecan-1 is present in high levels in many tumor types as well as in other disease states.
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Impact of Breathing 100% Oxygen on Radiation-Induced Cognitive Impairment.
Radiat. Res.
PUBLISHED: 10-23-2014
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Future space missions are expected to include increased extravehicular activities (EVAs) during which astronauts are exposed to high-energy space radiation while breathing 100% oxygen. Given that brain irradiation can lead to cognitive impairment, and that oxygen is a potent radiosensitizer, there is a concern that astronauts may be at greater risk of developing cognitive impairment when exposed to space radiation while breathing 100% O2 during an EVA. To address this concern, unanesthetized, unrestrained, young adult male Fischer 344 × Brown Norway rats were allowed to breathe 100% O2 for 30 min prior to, during and 2 h after whole-body irradiation with 0, 1, 3, 5 or 7 Gy doses of 18 MV X rays delivered from a medical linear accelerator at a dose rate of ?425 mGy/min. Irradiated and unirradiated rats breathing air (?21% O2) served as controls. Cognitive function was assessed 9 months postirradiation using the perirhinal cortex-dependent novel object recognition task. Cognitive function was not impaired until the rats breathing either air or 100% O2 received a whole-body dose of 7 Gy. However, at all doses cognitive function of the irradiated rats breathing 100% O2 was improved over that of the irradiated rats breathing air. These data suggest that astronauts are not at greater risk of developing cognitive impairment when exposed to space radiation while breathing 100% O2 during an EVA.
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Longitudinal Assessment of Concurrent Changes in Left Ventricular Ejection Fraction and Left Ventricular Myocardial Tissue Characteristics After Administration of Cardiotoxic Chemotherapies Using T1-Weighted and T2-Weighted Cardiovascular Magnetic Resonance.
Circ Cardiovasc Imaging
PUBLISHED: 10-01-2014
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In a murine anthracycline-related cardiotoxicity model, increases in cardiovascular magnetic resonance myocardial contrast-enhanced T1-weighted signal intensity are associated with myocellular injury and decreases with left ventricular ejection fraction. We sought to determine whether T1- and T2-weighted measures of signal intensity associate with decreases in left ventricular ejection fraction in human subjects receiving potentially cardiotoxic chemotherapy.
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Biomarkers of cardiovascular stress and subclinical atherosclerosis in the community.
Clin. Chem.
PUBLISHED: 09-18-2014
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Biomarkers of cardiovascular stress have been associated with incident cardiovascular outcomes. Their relations with measures of subclinical atherosclerosis, as assessed by carotid intima-media thickness, have not been well described.
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Effect of fludrocortisone acetate on chronic unexplained nausea and abdominal pain in children with orthostatic intolerance.
J. Pediatr. Gastroenterol. Nutr.
PUBLISHED: 09-16-2014
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We hypothesized that orthostatic intolerance (OI) is associated with gastric dysrhythmias, nausea, and abdominal pain, which improves using fludrocortisone to treat OI.
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What to expect from net reclassification improvement with three categories.
Stat Med
PUBLISHED: 08-31-2014
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The net reclassification improvement (NRI) has become a popular measure of incremental usefulness of markers added to risk prediction models. However, the expected magnitude of the three-category NRI is not well understood, leading researchers to rely on statistical significance. In this paper, we describe a slight modification to the original definition of the NRI, which weighs each reclassification by the number of categories by which a given individual is reclassified. This modification resolves some recent criticisms of the three-category NRI and at the same time has a minimal impact on its magnitude. Then we show that using this modified definition, the event and nonevent NRIs have simple interpretations as sums of changes in sensitivities and specificities calculated at the risk thresholds. We exploit this relationship to arrive at closed-form solutions for the NRI under normality within the event and nonevent subgroups. We observe that the size of the intermediate risk category and the event rate have limited impact on the magnitude of the NRI. As expected, the NRI increases with the strength of the added marker, and this relationship appears fairly proportional for markers with non-weak net effect size (above 0.25). Furthermore, we conclude that using the NRI as a metric, it is harder to improve models that already perform well. Copyright © 2014 John Wiley & Sons, Ltd.
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Covariate effect on constancy assumption in noninferiority clinical trials.
J Biopharm Stat
PUBLISHED: 07-19-2014
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Noninferiority (NI) clinical trials are getting a lot of attention of late due to their direct application in biosimilar studies. Because of the missing placebo arm, NI is an indirect approach to demonstrate efficacy of a test treatment. One of the key assumptions in the NI test is the constancy assumption, that is, that the effect of the reference treatment is the same in current NI trials as in historical superiority trials. However, if a covariate interacts with the treatment arms, then changes in distribution of this covariate will likely result in violation of constancy assumption. In this article, we propose four new NI methods and compare them with two existing methods to evaluate the change of background constancy assumption on the performance of these six methods. To achieve this goal, we study the impact of three elements-(1) strength of covariate, (2) degree of interaction between covariate and treatment, and (3) differences in distribution of the covariate between historical and current trials-on both the type I error rate and power using three different measures of association: difference, log relative risk, and log odds ratio. Based on this research, we recommend using a modified covariate-adjustment fixed margin method.
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Inference of equivalence for the ratio of two normal means with unspecified variances.
J Biopharm Stat
PUBLISHED: 07-18-2014
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Equivalence trials aim to demonstrate that new and standard treatments are equivalent within predefined clinically relevant limits. We focus on when inference of equivalence is made in terms of the ratio of two normal means. In the presence of unspecified variances, methods such as the likelihood-ratio test use sample estimates for those variances; Bayesian models integrate them out in the posterior distribution. These methods limit the knowledge on the extent to which equivalence is affected by variability of the parameter of interest. In this article, we propose a likelihood approach that retains the unspecified variances in the model and partitions the likelihood function into two components: F-statistic function for variances, and t-statistic function for the ratio of two means. By incorporating unspecified variances, the proposed method can help identify a numeric range of variances where equivalence is more likely to be achieved, which cannot be accomplished by current analysis methods. By partitioning the likelihood function into two components, the proposed method provides more inference information than a method that relies solely on one component. Using a published set of real example data, we show that the proposed method produces the same results as the likelihood-ratio test and is comparable to Bayesian analysis in the general case. In a special case where the ratio of two variances is directly proportional to the ratio of two means, the proposed method yields better results in inference about equivalence than either the likelihood-ratio test or the Bayesian method. Using a published set of real example data, the proposed likelihood method is shown to be a better alternative than current analysis methods for equivalence inference.
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Baseline levels, and changes over time in body mass index and fasting insulin, and their relationship to change in metabolic trait clustering.
Metab Syndr Relat Disord
PUBLISHED: 07-09-2014
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Multiple abnormal metabolic traits are found together or "cluster" within individuals more often than is predicted by chance. The individual and combined role of adiposity and insulin resistance (IR) on metabolic trait clustering is uncertain. We tested the hypothesis that change in trait clustering is a function of both baseline level and change in these measures.
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Shared decision-making among caregivers and health care providers of youth with type 1 diabetes.
J Clin Psychol Med Settings
PUBLISHED: 06-23-2014
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The present study aimed to examine perceptions of shared decision-making (SDM) in caregivers of youth with type 1 diabetes (T1D). Interview, survey data, and HbA1c assays were gathered from caregivers of 439 youth with T1D aged 3-18 years. Caregiver-report indicated high perceived SDM during medical visits. Multivariable linear regression indicated that greater SDM is associated with lower HbA1c, older child age, and having a pediatric endocrinologist provider. Multiple logistic regression found that caregivers who did not perceive having made any healthcare decisions in the past year were more likely to identify a non-pediatric endocrinologist provider and to report less optimal diabetes self-care. Findings suggest that youth whose caregivers report greater SDM may show benefits in terms of self-care and glycemic control. Future research should examine the role of youth in SDM and how best to identify youth and families with low SDM in order to improve care.
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Cellular response of the rat brain to single doses of (137)Cs ? rays does not predict its response to prolonged 'biologically equivalent' fractionated doses.
Int. J. Radiat. Biol.
PUBLISHED: 06-18-2014
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To determine if the brain's response to single doses predicts its response to 'biologically equivalent' fractionated doses.
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Use of renin-angiotensin inhibitors in people with renal artery stenosis.
Clin J Am Soc Nephrol
PUBLISHED: 06-05-2014
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People with atherosclerotic renal artery stenosis may benefit from renin-angiotensin inhibitors, angiotensin-converting enzyme inhibitors, and angiotensin-receptor blockers, but little is known about the factors associated with their use.
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Trends in incidence of type 1 diabetes among non-Hispanic white youth in the u.s., 2002-2009.
Diabetes
PUBLISHED: 06-04-2014
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The SEARCH for Diabetes in Youth Study prospectively identified youth aged <20 years with physician-diagnosed diabetes. Annual type 1 diabetes (T1D) incidence per 100,000 person-years (95% CI) overall, by age-group, and by sex were calculated for at-risk non-Hispanic white (NHW) youth from 2002 through 2009. Joinpoint and Poisson regression models were used to test for temporal trends. The age- and sex-adjusted incidence of T1D increased from 24.4/100,000 (95% CI 23.9-24.8) in 2002 to 27.4/100,000 (26.9-27.9) in 2009 (P for trend = 0.0008). The relative annual increase in T1D incidence was 2.72% (1.18-4.28) per year; 2.84% (1.12-4.58) per year for males and 2.57% (0.68-4.51) per year for females. After adjustment for sex, significant increases were found for youth aged 5-9 years (P = 0.0023), 10-14 years (P = 0.0008), and 15-19 years (P = 0.004) but not among 0-4-year-olds (P = 0.1862). Mean age at diagnosis did not change. The SEARCH study demonstrated a significant increase in the incidence of T1D among NHW youth from 2002 through 2009 overall and in all but the youngest age-group. Continued surveillance of T1D in U.S. youth to identify future trends in T1D incidence and to plan for health care delivery is warranted.
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Impact of farnesylation inhibitors on survival in Hutchinson-Gilford progeria syndrome.
Circulation
PUBLISHED: 05-02-2014
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Hutchinson-Gilford progeria syndrome is an ultrarare segmental premature aging disease resulting in early death from heart attack or stroke. There is no approved treatment, but starting in 2007, several recent single-arm clinical trials administered inhibitors of protein farnesylation aimed at reducing toxicity of the disease-producing protein progerin. No study assessed whether treatments influence patient survival. The key elements necessary for this analysis are a robust natural history of survival and comparison with a sufficiently large patient population that has been treated for a sufficient time period with disease-targeting medications.
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Graphical assessment of incremental value of novel markers in prediction models: From statistical to decision analytical perspectives.
Biom J
PUBLISHED: 04-24-2014
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New markers may improve prediction of diagnostic and prognostic outcomes. We aimed to review options for graphical display and summary measures to assess the predictive value of markers over standard, readily available predictors. We illustrated various approaches using previously published data on 3264 participants from the Framingham Heart Study, where 183 developed coronary heart disease (10-year risk 5.6%). We considered performance measures for the incremental value of adding HDL cholesterol to a prediction model. An initial assessment may consider statistical significance (HR = 0.65, 95% confidence interval 0.53 to 0.80; likelihood ratio p < 0.001), and distributions of predicted risks (densities or box plots) with various summary measures. A range of decision thresholds is considered in predictiveness and receiver operating characteristic curves, where the area under the curve (AUC) increased from 0.762 to 0.774 by adding HDL. We can furthermore focus on reclassification of participants with and without an event in a reclassification graph, with the continuous net reclassification improvement (NRI) as a summary measure. When we focus on one particular decision threshold, the changes in sensitivity and specificity are central. We propose a net reclassification risk graph, which allows us to focus on the number of reclassified persons and their event rates. Summary measures include the binary AUC, the two-category NRI, and decision analytic variants such as the net benefit (NB). Various graphs and summary measures can be used to assess the incremental predictive value of a marker. Important insights for impact on decision making are provided by a simple graph for the net reclassification risk.
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Use of composite endpoints in clinical trials.
Stat Med
PUBLISHED: 04-23-2014
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The success of a confirmatory clinical trial designed to demonstrate the efficacy of a new treatment is highly dependent on the choice of valid primary efficacy endpoint(s). The optimal clinical and statistical situation for the design of such a trial is one that starts with the selection of a single primary efficacy endpoint that completely characterizes the disease under study, admits the most efficient clinical and statistical evaluation of treatment effect, and provides clear and broad interpretation of drug effect. For diseases with multidimensional presentations, however, the selection of such an endpoint may not be possible, and so drug effectiveness is often characterized by the use of composite or multiple efficacy endpoint(s). The use of a composite endpoint with components that are only slightly correlated but not quite dissimilar in their recognized clinical relevance could lead to a more sensitive statistical test and thus, adequately powered trials with smaller sample size. This note discusses the utility of composite endpoints in clinical trials and some of the common approaches for dealing with multiplicity arising from their use. Copyright © 2014 John Wiley & Sons, Ltd.
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Multiplicity adjustments in testing for bioequivalence.
Stat Med
PUBLISHED: 04-22-2014
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Bioequivalence of two drugs is usually demonstrated by rejecting two one-sided null hypotheses using the two one-sided tests for pharmacokinetic parameters: area under the concentration-time curve (AUC) and maximum concentration (Cmax). By virtue of the intersection-union test, there is no need for multiplicity adjustment in testing the two one-sided null hypotheses within each parameter. However, the decision rule for bioequivalence often requires equivalence to be achieved simultaneously on both parameters that contain four one-sided null hypotheses together; without adjusting for multiplicity, the family wise error rate (FWER) could fail to be controlled at the nominal type-I error rate ?. The multiplicity issue for bioequivalence in this regard is scarcely discussed in the literature. To address this issue, we propose two approaches including a closed test procedure that controls FWER for the simultaneous AUC and Cmax bioequivalence and requires no adjustment of the type-I error, and an alpha-adaptive sequential testing (AAST) that controls FWER by pre-specifying the significance level on AUC (?1 ) and obtaining it for Cmax (?2 ) adaptively after testing of AUC. While both methods control FWER, the closed test requires testing of eight intersection null hypotheses each at ?, and AAST is at times accomplished through a slight deduction in ?1 and no deduction in ?2 relative to ?. The latter considers equivalence reached in AUC a higher importance than that in Cmax. Illustrated with published data, the two approaches, although operate differently, can lead to the same substantive conclusion and are better than a traditional method like Bonferroni adjustment. Copyright © 2014 John Wiley & Sons, Ltd.
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High plasma folate is negatively associated with leukocyte telomere length in Framingham Offspring cohort.
Eur J Nutr
PUBLISHED: 04-16-2014
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Shortening of telomeres, the protective structures at the ends of eukaryotic chromosomes, is associated with age-related pathologies. Telomere length is influenced by DNA integrity and DNA and histone methylation. Folate plays a role in providing precursors for nucleotides and methyl groups for methylation reactions and has the potential to influence telomere length.
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Trends in the prevalence of ketoacidosis at diabetes diagnosis: the SEARCH for diabetes in youth study.
Pediatrics
PUBLISHED: 03-31-2014
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To estimate temporal changes in the prevalence of diabetic ketoacidosis (DKA) at diagnosis of type 1 or type 2 diabetes in youth and to explore factors associated with its occurrence.
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Glycated hemoglobin measurement and prediction of cardiovascular disease.
JAMA
PUBLISHED: 03-27-2014
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The value of measuring levels of glycated hemoglobin (HbA1c) for the prediction of first cardiovascular events is uncertain.
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Application of new cholesterol guidelines to a population-based sample.
N. Engl. J. Med.
PUBLISHED: 03-19-2014
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The 2013 guidelines of the American College of Cardiology and the American Heart Association (ACC-AHA) for the treatment of cholesterol expand the indications for statin therapy for the prevention of cardiovascular disease.
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Change in adiposity minimally affects the lipid profile in youth with recent onset type 1 diabetes.
Pediatr Diabetes
PUBLISHED: 03-18-2014
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Dyslipidemia contributes to the increased risk of cardiovascular disease in persons with type 1 diabetes (T1D). Weight control is commonly recommended as a treatment for dyslipidemia. However, the extent to which decreases in weight affect the lipid profile in youth with T1D is not known. Therefore, we tested the hypothesis that decreases in body mass index z-score (BMIz) were associated with concomitant changes in the lipid profile in youth with T1D.
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Assessing endothelial dysfunction in adolescents and young adults with type 1 diabetes mellitus using a non-invasive heat stimulus.
Pediatr Diabetes
PUBLISHED: 03-13-2014
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Microvascular dysfunction is a key event in the development of atherosclerosis, which predates the clinical manifestations of vascular disease including stroke and myocardial infarction. Dysfunction of the microvasculature can be measured as a decreased microperfusion in response to heat.
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Risk estimation for recurrent Clostridium difficile infection based on clinical factors.
Clin. Infect. Dis.
PUBLISHED: 03-05-2014
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The incidence of Clostridium difficile infection (CDI) has risen dramatically during the last decade. Although patients respond well to medical therapy such as vancomycin, 20%-30% of patients treated suffer a recurrence of CDI.
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Longitudinal association between television watching and computer use and risk markers in diabetes in the SEARCH for Diabetes in Youth Study.
Pediatr Diabetes
PUBLISHED: 02-26-2014
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The study provides evidence of the longitudinal association between screen time with hemoglobin A1c (HbA1c) and cardiovascular risk markers among youth with type 1 diabetes (T1D) and type 2 diabetes (T2D).
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One-year outcomes of out-of-hospital administration of intravenous glucose, insulin, and potassium (GIK) in patients with suspected acute coronary syndromes (from the IMMEDIATE [Immediate Myocardial Metabolic Enhancement During Initial Assessment and Treatment in Emerge
Am. J. Cardiol.
PUBLISHED: 02-21-2014
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The Immediate Myocardial Metabolic Enhancement During Initial Assessment and Treatment in Emergency care Trial of very early intravenous glucose-insulin-potassium (GIK) for acute coronary syndromes (ACS) in out-of-hospital emergency medical service (EMS) settings showed 80% reduction in infarct size at 30 days, suggesting potential longer-term benefits. Here we report 1-year outcomes. Prespecified 1-year end points of this randomized, placebo-controlled, double-blind, effectiveness trial included all-cause mortality and composites including cardiac arrest, mortality, or hospitalization for heart failure (HF). Of 871 participants randomized to GIK versus placebo, death occurred within 1 year in 11.6% versus 13.5%, respectively (unadjusted hazard ratio [HR] 0.83, 95% confidence interval [CI] 0.57 to 1.23, p = 0.36). The composite of cardiac arrest or 1-year mortality was 12.8% versus 17.0% (HR 0.71, 95% CI 0.50 to 1.02, p = 0.06). The composite of hospitalization for HF or mortality within 1 year was 17.2% versus 17.2% (HR 0.98, 95% CI 0.70 to 1.37, p = 0.92). The composite of mortality, cardiac arrest, or HF hospitalization within 1 year was 18.1% versus 20.4% (HR 0.85, 95% CI 0.62 to 1.16, p = 0.30). In patients presenting with suspected ST elevation myocardial infarction, HRs for 1-year mortality and the 3 composites were, respectively, 0.65 (95% CI 0.33 to 1.27, p = 0.21), 0.52 (95% CI 0.30 to 0.92, p = 0.03), 0.63 (95% CI 0.35 to 1.16, p = 0.14), and 0.51 (95% CI 0.30 to 0.87, p = 0.01). In patients with suspected acute coronary syndromes, serious end points generally were lower with GIK than placebo, but the differences were not statistically significant. However, in those with ST elevation myocardial infarction, the composites of cardiac arrest or 1-year mortality, and of cardiac arrest, mortality, or HF hospitalization within 1 year, were significantly reduced.
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Standard forward-viewing colonoscopy versus full-spectrum endoscopy: an international, multicentre, randomised, tandem colonoscopy trial.
Lancet Oncol.
PUBLISHED: 02-20-2014
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Although colonoscopy is the accepted standard for detection of colorectal adenomas and cancers, many adenomas and some cancers are missed. To avoid interval colorectal cancer, the adenoma miss rate of colonoscopy needs to be reduced by improvement of colonoscopy technique and imaging capability. We aimed to compare the adenoma miss rates of full-spectrum endoscopy colonoscopy with those of standard forward-viewing colonoscopy.
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Quantifying cardiometabolic risk using modifiable non-self-reported risk factors.
Am J Prev Med
PUBLISHED: 02-18-2014
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Sensitive general cardiometabolic risk assessment tools of modifiable risk factors would be helpful and practical in a range of primary prevention interventions or for preventive health maintenance.
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Assessing the incremental predictive performance of novel biomarkers over standard predictors.
Stat Med
PUBLISHED: 02-13-2014
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It is unclear to what extent the incremental predictive performance of a novel biomarker is impacted by the method used to control for standard predictors. We investigated whether adding a biomarker to a model with a published risk score overestimates its incremental performance as compared to adding it to a multivariable model with individual predictors (or a composite risk score estimated from the sample of interest) and to a null model. We used 1000 simulated datasets (with a range of risk factor distributions and event rates) to compare these methods, using the continuous net reclassification index (NRI), the integrated discrimination index (IDI), and change in the C-statistic as discrimination metrics. The new biomarker was added to the following: null model, model including a published risk score, model including a composite risk score estimated from the sample of interest, and multivariable model with individual predictors. We observed a gradient in the incremental performance of the biomarker, with the null model resulting in the highest predictive performance of the biomarker and the model using individual predictors resulting in the lowest (mean increases in C-statistic between models without and with the biomarker: 0.261, 0.085, 0.030, and 0.031; NRI: 0.767, 0.621, 0.513, and 0.530; IDI: 0.153, 0.093, 0.053 and 0.057, respectively). These findings were supported by the Framingham Study data predicting atrial fibrillation using novel biomarkers. We recommend that authors report the effect of a new biomarker after controlling for standard predictors modeled as individual variables.
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Cardiovascular health in adolescents with type 1 diabetes: the SEARCH CVD study.
Pediatr Diabetes
PUBLISHED: 01-22-2014
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In their Strategic Impact Goal Statement, the American Heart Association focused on primordial prevention of cardiovascular risk factors by defining metrics for ideal cardiovascular health (ICH). The prevalence of ICH among youth with type 1 diabetes is unknown. Youth with type 1 diabetes face an increased risk of cardiovascular disease (CVD) as they age. The purpose of this report was to examine the prevalence of ICH in a population of youth with type 1 diabetes and to examine the association of ICH with measures of cardiovascular structure and function.
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Inference of bioequivalence for log-normal distributed data with unspecified variances.
Stat Med
PUBLISHED: 01-09-2014
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Two drugs are bioequivalent if the ratio of a pharmacokinetic (PK) parameter of two products falls within equivalence margins. The distribution of PK parameters is often assumed to be log-normal, therefore bioequivalence (BE) is usually assessed on the difference of logarithmically transformed PK parameters (?). In the presence of unspecified variances, test procedures such as two one-sided tests (TOST) use sample estimates for those variances; Bayesian models integrate them out in the posterior distribution. These methods limit our knowledge on the extent that inference about BE is affected by the variability of PK parameters. In this paper, we propose a likelihood approach that retains the unspecified variances in the model and partitions the entire likelihood function into two components: F-statistic function for variances and t-statistic function for ?. Demonstrated with published real-life data, the proposed method not only produces results that are same as TOST and comparable with Bayesian method but also helps identify ranges of variances, which could make the determination of BE more achievable. Our findings manifest the advantages of the proposed method in making inference about the extent that BE is affected by the unspecified variances, which cannot be accomplished either by TOST or Bayesian method.
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No association of dietary fiber intake with inflammation or arterial stiffness in youth with type 1 diabetes.
J. Diabetes Complicat.
PUBLISHED: 01-08-2014
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To examine the association of dietary fiber intake with inflammation and arterial stiffness among youth with type 1 diabetes (T1D) in the US.
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Sensitivity and Specificity Can Change in Opposite Directions When New Predictive Markers Are Added to Risk Models.
Med Decis Making
PUBLISHED: 12-30-2013
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When comparing prediction models, it is essential to estimate the magnitude of change in performance rather than rely solely on statistical significance. In this paper we investigate measures that estimate change in classification performance, assuming 2-group classification based on a single risk threshold. We study the value of a new biomarker when added to a baseline risk prediction model. First, simulated data are used to investigate the change in sensitivity and specificity (?Se and ?Sp). Second, the influence of ?Se and ?Sp on the net reclassification improvement (NRI; sum of ?Se and ?Sp) and on decision-analytic measures (net benefit or relative utility) is studied. We assume normal distributions for the predictors and assume correctly specified models such that the extended model has a dominating receiver operating characteristic curve relative to the baseline model. Remarkably, we observe that even when a strong marker is added it is possible that either sensitivity (for thresholds below the event rate) or specificity (for thresholds above the event rate) decreases. In these cases, decision-analytic measures provide more modest support for improved classification than NRI, even though all measures confirm that adding the marker improved classification accuracy. Our results underscore the necessity of reporting ?Se and ?Sp separately. When a single summary is desired, decision-analytic measures allow for a simple incorporation of the misclassification costs.
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IRP2 regulates breast tumor growth.
Cancer Res.
PUBLISHED: 11-27-2013
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Experimental and epidemiological evidence suggest that dysregulation of proteins involved in iron metabolism plays a critical role in cancer. The mechanisms by which cancer cells alter homeostatic iron regulation are just beginning to be understood. Here we demonstrate that iron regulatory protein 2 (IRP2) plays a key role in iron accumulation in breast cancer. Although both IRP1 and IRP2 are over-expressed in breast cancer, the overexpression of IRP2, but not IRP1, is associated with decreased ferritin H and increased transferrin receptor 1 (TfR1). Knock-down of IRP2 in triple negative MDA-MB-231 human breast cancer cells increases ferritin H expression and decreases TfR1 expression, resulting in a decrease in the labile iron pool. Further, IRP2 knockdown reduces growth of MDA-MB-231 cells in the mouse mammary fat pad. Gene expression microarray profiles of breast cancer patients demonstrate that increased IRP2 expression is associated with high grade cancer. Increased IRP2 expression is observed in luminal A, luminal B and basal breast cancer subtypes, but not in breast tumors of the ERBB2 molecular subtype. These results suggest that dysregulation of IRP2 is an early nodal point underlying altered iron metabolism in breast cancer and may contribute to poor outcome of some breast cancer patients.
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Diabetes Self-Management Education Patterns in a US Population-Based Cohort of Youth With Type 1 Diabetes.
Diabetes Educ
PUBLISHED: 11-18-2013
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PurposeThe purpose of this study is to describe (1) the receipt of diabetes self-management education (DSME) in a large, diverse cohort of US youth with type 1 diabetes (T1DM), (2) the segregation of self-reported DSME variables into domains, and (3) the demographic and clinical characteristics of youth who receive DSME.MethodsData are from the US population-based cohort SEARCH for Diabetes in Youth. A cross-sectional analysis was employed using data from 1273 youth <20 years of age at the time of diagnosis of T1DM. Clusters of 19 self-reported DSME variables were derived using factor analysis, and their associations with demographic and clinical characteristics were evaluated using polytomous logistic regression.ResultsNearly all participants reported receiving DSME content consistent with "survival skills" (eg, target blood glucose and what to do for low or high blood glucose), yet gaps in continuing education were identified (eg, fewer than half of the participants reported receiving specific medical nutrition therapy recommendations). Five DSME clusters were explored: receipt of specific MNT recommendations, receipt of diabetes information resources, receipt of clinic visit information, receipt of specific diabetes information, and met with educator or nutritionist. Factor scores were significantly associated with demographic and clinical characteristics, including race/ethnicity, socioeconomic status, and diabetes self-management practices.ConclusionsHealth care providers should work together to address reported gaps in DSME to improve patient care.
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Stenting and medical therapy for atherosclerotic renal-artery stenosis.
N. Engl. J. Med.
PUBLISHED: 11-18-2013
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Atherosclerotic renal-artery stenosis is a common problem in the elderly. Despite two randomized trials that did not show a benefit of renal-artery stenting with respect to kidney function, the usefulness of stenting for the prevention of major adverse renal and cardiovascular events is uncertain.
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Left ventricular hypertrophy patterns and incidence of heart failure with preserved versus reduced ejection fraction.
Am. J. Cardiol.
PUBLISHED: 09-17-2013
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Higher left ventricular (LV) mass, wall thickness, and internal dimension are associated with increased heart failure (HF) risk. Whether different LV hypertrophy patterns vary with respect to rates and types of HF incidence is unclear. In this study, 4,768 Framingham Heart Study participants (mean age 50 years, 56% women) were classified into 4 mutually exclusive LV hypertrophy pattern groups (normal, concentric remodeling, concentric hypertrophy, and eccentric hypertrophy) using American Society of Echocardiography-recommended thresholds of echocardiographic LV mass indexed to body surface area and relative wall thickness, and these groups were related to HF incidence. Whether risk for HF types (HF with reduced ejection fraction [<45%] vs preserved ejection fraction [?45%]) varied by hypertrophy pattern was then evaluated. On follow-up (mean 21 years), 458 participants (9.6%, 250 women) developed new-onset HF. The age- and gender-adjusted 20-year HF incidence increased from 6.96% in the normal left ventricle group to 8.67%, 13.38%, and 15.27% in the concentric remodeling, concentric hypertrophy, and eccentric hypertrophy groups, respectively. After adjustment for co-morbidities and incident myocardial infarction, LV hypertrophy patterns were associated with higher HF incidence relative to the normal left ventricle group (p = 0.0002); eccentric hypertrophy carried the greatest risk (hazard ratio [HR] 1.89, 95% confidence interval [CI] 1.41 to 2.54), followed by concentric hypertrophy (HR 1.40, 95% CI 1.04 to 1.87). Participants with eccentric hypertrophy had a higher propensity for HF with reduced ejection fraction (HR 2.23, 95% CI 1.48 to 3.37), whereas those with concentric hypertrophy were more prone to HF with preserved ejection fraction (HR 1.66, 95% CI 1.09 to 2.51). In conclusion, in this large community-based sample, HF risk varied by LV hypertrophy pattern, with eccentric and concentric hypertrophy predisposing to HF with reduced and preserved ejection fraction, respectively.
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Impact of Glycemic Control on Heart Rate Variability in Youth with Type 1 Diabetes: The SEARCH CVD Study.
Diabetes Technol. Ther.
PUBLISHED: 09-06-2013
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Abstract Aim: This study explored the role of glycemic control on cardiac autonomic function, measured by heart rate variability (HRV), in youth with type 1 diabetes. Patients and Methods: A retrospective cohort of 345 youth with type 1 diabetes (mean age, 18.5 years; duration, 10 years) participating in the SEARCH for Diabetes in Youth study were enrolled in the ancillary SEARCH Cardiovascular Disease (CVD) study. Anthropometric, metabolic, and HRV parameters were collected at the current research visit. Glycemic control over time was assessed by the mean glycated hemoglobin (A1c) levels collected over the past 6 years. Multiple linear regression analysis assessed the association between A1c over time and HRV parameters, independent of demographic and CVD risk factors. Participants were categorized into four glycemic control categories based on their mean A1c over time: Group 1, optimal (mean A1c, ?7.4%); Group 2 (mean A1c, 7.5-8.4%); Group 3 (mean A1c, 8.5-9.4%), and Group 4, poor (mean A1c, ?9.5%), and a linear trend was explored across these categories. Results: For every 1% increase in the average A1c over 6 years there was a 5% decrease in the SD of the normal RR interval (SDNN) (P=0.02) and 7% decrease in the root mean square successive difference of the RR interval (RMSSD) (P=0.02), independent of demographic and traditional CVD risk factors. A dose-response relationship between worsening glucose control categories and measures of overall reduced HRV was found. Conclusions: Chronic hyperglycemia is the main determinant of early cardiac autonomic dysfunction, manifested as reduced overall HRV and parasympathetic loss, among youth with type 1 diabetes.
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"Causes" of pesticide safety behavior change in Latino farmworker families.
Am J Health Behav
PUBLISHED: 08-30-2013
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To identify the source of behavior change resulting from a health education intervention focused on pesticide safety.
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Heparan sulfate in the nucleus and its control of cellular functions.
Matrix Biol.
PUBLISHED: 08-29-2013
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Heparan sulfate proteoglycans (HSPG) are present on the cell surface, within the extracellular matrix, and as soluble molecules in tissues and blood. HSPGs are known to regulate a wide range of cellular functions predominantly by serving as co-receptors for growth factors, chemokines, and other regulatory proteins that control inflammation, wound healing and tumorigenesis. Several studies have demonstrated the presence of heparan sulfate (HS) or HSPGs in the cell nucleus, but little attention has been focused on their role there. However, evidence is mounting that nuclear HS and HSPGs have important regulatory functions that impact the cell cycle, proliferation, transcription and transport of cargo to the nucleus. The discovery of proteoglycans in the nucleus extends the list of "non-traditional nuclear proteins" that includes, for example, cytoskeletal proteins such as actin and tubulin, and growth factors and their receptors. In this review we discuss the discovery and fascinating roles of HS and HSPGs in the nucleus and propose a number of key questions that remain to be addressed.
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Feasibility of using a community-supported agriculture program to improve fruit and vegetable inventories and consumption in an underresourced urban community.
Prev Chronic Dis
PUBLISHED: 08-17-2013
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Direct-to-consumer marketing efforts, such as community-supported agriculture (CSA), have been proposed as a solution for disparities in fruit and vegetable consumption. Evaluations of such efforts have been limited. The objective of this study was to test the feasibility of a CSA intervention to increase household inventory of fruits and vegetables and fruit and vegetable consumption of residents of an underresourced community.
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Chemotherapy stimulates syndecan-1 shedding: A potentially negative effect of treatment that may promote tumor relapse.
Matrix Biol.
PUBLISHED: 08-08-2013
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In patients with multiple myeloma, the heparan sulfate proteoglycan syndecan-1 (CD138) is shed from the surface of tumor cells and accumulates in the serum and within the extracellular matrix of the bone marrow where it promotes tumor growth and metastasis. In the present study we discovered that commonly used anti-myeloma drugs stimulate syndecan-1 shedding both in vitro and in animals bearing myeloma tumors. Enhanced shedding is accompanied by increased syndecan-1 synthesis prior to drug induced tumor cell death. Addition of a caspase inhibitor blocks the drug-induced shedding of syndecan-1 in vitro indicating that shedding is linked to the onset of apoptosis. ADAM inhibitors or siRNA targeting ADAMs blocked drug-induced shedding suggesting that upregulation or activation of ADAMs is responsible for cleaving syndecan-1 from the tumor cell surface. These results reveal that myeloma chemotherapy stimulates synthesis and shedding of syndecan-1, a potentially negative side effect that may lead to the accumulation of high levels of syndecan-1 to establish a microenvironment that nurtures relapse and promotes tumor progression. Interestingly, we also found that chemotherapeutic drugs stimulated syndecan-1 shedding from pancreatic cancer cells as well, indicating that drug-induced shedding of syndecan-1 may occur in many cancer types. Overall, our results indicate that the use of metalloproteinase inhibitors (to inhibit syndecan-1 shedding) in combination with chemotherapy may represent a novel therapeutic strategy to prevent re-establishment of a microenvironment conducive for tumor relapse.
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Chronic Kidney Disease Defined by Cystatin C Predicts Mobility Disability and Changes in Gait Speed: The Framingham Offspring Study.
J. Gerontol. A Biol. Sci. Med. Sci.
PUBLISHED: 08-02-2013
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As creatinine-based estimates of renal function are inaccurate in older adults, an alternative is an estimated glomerular filtration rate (eGFRcys) based on cystatin C. We examined the prospective association between chronic kidney disease (CKDcys) as determined by eGFRcys with the primary outcome of incident mobility disability and the secondary outcome of change in gait speed.
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High-density lipoproteins: a consensus statement from the National Lipid Association.
J Clin Lipidol
PUBLISHED: 07-29-2013
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For >4 decades it has been recognized that elevated serum levels of high-density lipoprotein cholesterol (HDL-C) are associated with reduced risk of cardiovascular disease (CVD) and its sequelae. Many prospective observational studies performed around the world have confirmed an inverse relationship between HDL-C and cardiovascular risk in people irrespective of sex, race, or ethnicity. Consequently, it was assumed that, by extension, raising HDL-C through lifestyle modification and pharmacologic intervention would reduce risk of CVD. Animal studies are consistent with this assumption. Lipid treatment guidelines around the world promoted the recognition of HDL-C as a therapeutic target, especially in high-risk patients. Some post hoc analyses from randomized controlled trials also suggest that raising HDL-C beneficially affects the risk of CVD. However, a number of recent randomized studies putatively designed to test the "HDL hypothesis" have failed to show benefit. The results of these trials have caused many clinicians to question whether HDL-C is a legitimate therapeutic target. In response to the many questions and uncertainties raised by the results of these trials, the National Lipid Association convened an expert panel to evaluate the current status of HDL-C as a therapeutic target; to review the current state of knowledge of HDL particle structure, composition, and function; and to identify the salient questions yet to be answered about the role of HDL in either preventing or contributing to atherosclerotic disease. The expert panels conclusions and clinical recommendations are summarized herein. The panel concludes that, although low HDL-C identifies patients at elevated risk, and much investigation suggests that HDL may play a variety of antiatherogenic roles, HDL-C is not a therapeutic target at the present time. Risk stratified atherogenic lipoprotein burden (low-density lipoprotein cholesterol and non-HDL-C) should remain the primary and secondary targets of therapy in patients at risk, as described by established guidelines. The National Lipid Association emphasizes that rigorous research into the biology and clinical significance of low HDL-C should continue. The development of novel drugs designed to modulate the serum levels and functionality of HDL particles should also continue. On the basis of an enormous amount of basic scientific and clinical investigation, a considerable number of reasons support the need to continue to investigate the therapeutic effect of modulating HDL structure and function.
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Albuminuria according to status of autoimmunity and insulin sensitivity among youth with type 1 and type 2 diabetes.
Diabetes Care
PUBLISHED: 07-11-2013
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To evaluate whether etiologic diabetes type is associated with the degree of albuminuria in children with diabetes. RESEARCH DESIGN AND METHODS SEARCH: is an observational, longitudinal study of children with diabetes. Youth with newly diagnosed diabetes were classified according to diabetes autoantibody (DAA) status and presence of insulin resistance. We defined insulin resistance as an insulin sensitivity score <25th percentile for the United States general youth population. DAA status was based on positivity for the 65-kD isoform of glutamate decarboxylase and insulinoma-associated protein 2 antigens. The four etiologic diabetes type groups were as follows: DAA(+)/insulin-sensitive (IS) (n = 1,351); DAA(+)/insulin-resistant (IR) (n = 438); DAA(-)/IR (n = 379); and DAA(-)/IS (n = 233). Urinary albumin:creatinine ratio (UACR) was measured from a random urine specimen. Multivariable regression analyses assessed the independent relationship between the four diabetes type groups and magnitude of UACR.
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Nutritional factors and preservation of C-peptide in youth with recently diagnosed type 1 diabetes: SEARCH Nutrition Ancillary Study.
Diabetes Care
PUBLISHED: 06-27-2013
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To test the novel hypothesis that nutritional factors previously associated with type 1 diabetes etiology or with insulin secretion are prospectively associated with fasting C-peptide (FCP) concentration among youth recently diagnosed with type 1 diabetes.
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Cardiovascular Disease Risk Assessment: Insights from Framingham.
Glob Heart
PUBLISHED: 06-11-2013
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Cardiovascular disease (CVD) is among the leading causes of death and disability worldwide. Since its beginning, the Framingham study has been a leader in identifying CVD risk factors. Clinical trials have demonstrated that when the modifiable risk factors are treated and corrected, the chances of CVD occurring can be reduced. The Framingham study also recognized that CVD risk factors are multifactorial and interact over time to produce CVD. In response, Framingham investigators developed the Framingham Risk Functions (also called Framingham Risk Scores) to evaluate the chance or likelihood of developing CVD in individuals. These functions are multivariate functions (algorithms) that combine the information in CVD risk factors such as sex, age, systolic blood pressure, total cholesterol, high-density lipoprotein cholesterol, smoking behavior, and diabetes status to produce an estimate (or risk) of developing CVD or a component of CVD (such as coronary heart disease, stroke, peripheral vascular disease, or heart failure) over a fixed time, for example, the next 10 years. These estimates of CVD risk are often major inputs in recommending drug treatments such as cholesterol-lowering drugs.
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Correlates of medical nutrition therapy and cardiovascular outcomes in youth with type 1 diabetes.
J Nutr Educ Behav
PUBLISHED: 06-04-2013
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To examine whether the types of medical nutrition therapies (MNTs) taught to and used by youth with type 1 diabetes (T1D) vary by sociodemographic characteristics and cardiovascular (CVD) risk factors.
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Heparanase inhibits osteoblastogenesis and shifts bone marrow progenitor cell fate in myeloma bone disease.
Bone
PUBLISHED: 04-15-2013
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A major cause of morbidity in patients with multiple myeloma is the development and progression of bone disease. Myeloma bone disease is characterized by rampant osteolysis in the presence of absent or diminished bone formation. Heparanase, an enzyme that acts both at the cell-surface and within the extracellular matrix to degrade polymeric heparan sulfate chains, is upregulated in a variety of human cancers including multiple myeloma. We and others have shown that heparanase enhances osteoclastogenesis and bone loss. However, increased osteolysis is only one element of the spectrum of myeloma bone disease. In the present study, we hypothesized that heparanase would also affect mesenchymal cells in the bone microenvironment and investigated the effect of heparanase on the differentiation of osteoblast/stromal lineage cells. Using a combination of molecular, biochemical, cellular and in vivo approaches, we demonstrated that heparanase significantly inhibited osteoblast differentiation and mineralization, and reduced bone formation in vivo. In addition, heparanase shifts the differentiation potential of osteoblast progenitors from osteoblastogenesis to adipogenesis. Mechanistically, this shift in cell fate is due, at least in part, to heparanase-enhanced production and secretion of the Wnt signaling pathway inhibitor DKK1 by both osteoblast progenitors and myeloma cells. Collectively, these data provide important new insights into the role of heparanase in all aspects of myeloma bone disease and strongly support the use of heparanase inhibitors in the treatment of multiple myeloma.
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Effect of type 1 diabetes on carotid structure and function in adolescents and young adults: the SEARCH CVD study.
Diabetes Care
PUBLISHED: 04-05-2013
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Type 1 diabetes mellitus causes increased carotid intima-media thickness (IMT) in adults. We evaluated IMT in young subjects with type 1 diabetes.
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Sex-specific differences in the predictive value of cholesterol homeostasis markers and 10-year cardiovascular disease event rate in Framingham Offspring Study participants.
J Am Heart Assoc
PUBLISHED: 03-26-2013
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Available data are inconsistent regarding factors influencing plasma cholesterol homeostasis marker concentrations and their value in predicting subsequent cardiovascular disease (CVD) events.
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The influence of exposure to maternal diabetes in utero on the rate of decline in ?-cell function among youth with diabetes.
J. Pediatr. Endocrinol. Metab.
PUBLISHED: 03-24-2013
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Abstract We explored the influence of exposure to maternal diabetes in utero on ? cell decline measured by fasting C-peptide (FCP) among 1079 youth <20 years with diabetes, including 941 with type 1 and 138 with type 2 diabetes. Youths exposed to maternal diabetes had FCP levels that were 17% lower among youth with type 2 diabetes [95% confidence interval (CI): -34%, +6%] and 15% higher among youth with type 1 diabetes (95%CI: -14%, +55%) than their unexposed counterparts, although differences were not statistically significant (p=0.13 and p=0.35, respectively). Exposure to maternal diabetes was not associated with FCP decline in youth with type 2 (p=0.16) or type 1 diabetes (p=0.90); nor was the effect of in utero exposure on FCP modified by diabetes type. Findings suggest that exposure to maternal diabetes in utero may not be an important determinant of short-term ?-cell function decline in youth with type 1 or type 2 diabetes.
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Impact of correlation on predictive ability of biomarkers.
Stat Med
PUBLISHED: 03-22-2013
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In this paper, we investigate how the correlation structure of independent variables affects the discrimination of risk prediction model. Using multivariate normal data and binary outcome, we prove that zero correlation among predictors is often detrimental for discrimination in a risk prediction model and negatively correlated predictors with positive effect sizes are beneficial. A very high multiple R-squared from regressing the new predictor on the old ones can also be beneficial. As a practical guide to new variable selection, we recommend to select predictors that have negative correlation with the risk score based on the existing variables. This step is easy to implement even when the number of new predictors is large. We illustrate our results by using real-life Framingham data suggesting that the conclusions hold outside of normality. The findings presented in this paper might be useful for preliminary selection of potentially important predictors, especially is situations where the number of predictors is large. Copyright ©?2013 John Wiley & Sons, Ltd.
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Association of smoking cessation and weight change with cardiovascular disease among adults with and without diabetes.
JAMA
PUBLISHED: 03-14-2013
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Smoking cessation reduces the risks of cardiovascular disease (CVD), but weight gain that follows quitting smoking may weaken the CVD benefit of quitting.
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Re-using Mini-Sentinel data following rapid assessments of potential safety signals via modular analytic programs.
Pharmacoepidemiol Drug Saf
PUBLISHED: 03-07-2013
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The U.S. Food and Drug Administration (FDA)s Mini-Sentinel pilot has created a distributed data system with over 125 million lives and nearly 350 million person-years of observation time. The pilot allows the FDA to use modular analytic programs to assess suspected safety signals quickly. The FDA convened a committee to assess the implications of such rapid assessments on subsequent analyses of the same product-outcome pair using the same data. The committee offers several non-binding recommendations based on the strength of the knowledge of the suspected association before running the analysis: signal generation (an analysis with no prior), signal refinement (an analysis with a weak or moderate prior), and signal evaluation (an analysis with a strong prior). The committee believes that modular programs (MPs) are most useful for signal refinement. If MPs are used for analyses with no or weak/moderate priors, the committee members generally agree that the data may be re-used if certain conditions are met. When there is a strong prior, the committee recommends that a protocol-based assessment be used; Mini-Sentinel data may be analyzed by MPs and re-used only under very uncommon circumstances. The committee agrees that any subsequent assessment of the same product-outcome pair that follows an MP analysis should not be interpreted as independent confirmation of the association, such as would be established via replication of the same product-outcome association in two different populations. Instead, the follow-up assessment should be interpreted as an analysis that has reduced insofar as possible systematic errors that may have been present or residual in the original MP analysis. The committee also discussed how this general framework may apply to two completed rapid assessments of dabigatran and bleeding risk and of olmesartan and celiac disease risk.
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Reduced heart rate variability is associated with increased arterial stiffness in youth with type 1 diabetes: the SEARCH CVD study.
Diabetes Care
PUBLISHED: 02-22-2013
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Reduced heart rate variability (HRV) and increased arterial stiffness (AS) are both present in youth with type 1 diabetes. However, it is unclear whether they are associated and whether their association is independent of cardiovascular disease (CVD) risk factors.
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Heparanase regulates secretion, composition, and function of tumor cell-derived exosomes.
J. Biol. Chem.
PUBLISHED: 02-21-2013
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Emerging evidence indicates that exosomes play a key role in tumor-host cross-talk and that exosome secretion, composition, and functional capacity are altered as tumors progress to an aggressive phenotype. However, little is known regarding the mechanisms that regulate these changes. Heparanase is an enzyme whose expression is up-regulated as tumors become more aggressive and is associated with enhanced tumor growth, angiogenesis, and metastasis. We have discovered that in human cancer cells (myeloma, lymphoblastoid, and breast cancer), when expression of heparanase is enhanced or when tumor cells are exposed to exogenous heparanase, exosome secretion is dramatically increased. Heparanase enzyme activity is required for robust enhancement of exosome secretion because enzymatically inactive forms of heparanase, even when present in high amounts, do not dramatically increase exosome secretion. Heparanase also impacts exosome protein cargo as reflected by higher levels of syndecan-1, VEGF, and hepatocyte growth factor in exosomes secreted by heparanase-high expressing cells as compared with heparanase-low expressing cells. In functional assays, exosomes from heparanase-high cells stimulated spreading of tumor cells on fibronectin and invasion of endothelial cells through extracellular matrix better than did exosomes secreted by heparanase-low cells. These studies reveal that heparanase helps drive exosome secretion, alters exosome composition, and facilitates production of exosomes that impact both tumor and host cell behavior, thereby promoting tumor progression.
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Impact of enzyme replacement therapy on survival in adults with Pompe disease: results from a prospective international observational study.
Orphanet J Rare Dis
PUBLISHED: 02-04-2013
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BACKGROUND: Pompe disease is a rare metabolic myopathy for which disease-specific enzyme replacement therapy (ERT) has been available since 2006. ERT has shown efficacy concerning muscle strength and pulmonary function in adult patients. However, no data on the effect of ERT on the survival of adult patients are currently available. The aim of this study was to assess the effect of ERT on survival in adult patients with Pompe disease. METHODS: Data were collected as part of an international observational study conducted between 2002 and 2011, in which patients were followed on an annual basis. Time-dependent Coxs proportional hazards models were used for univariable and multivariable analyses. RESULTS: Overall, 283 adult patients with a median age of 48 years (range, 19 to 81 years) were included in the study. Seventy-two percent of patients started ERT at some time during follow-up, and 28% never received ERT. During follow-up (median, 6 years; range, 0.04 to 9 years), 46 patients died, 28 (61%) of whom had never received ERT. After adjustment for age, sex, country of residence, and disease severity (based on wheelchair and ventilator use), ERT was positively associated with survival (hazard ratio, 0.41; 95% CI, 0.19 to 0.87). CONCLUSION: This prospective study was the first to demonstrate the positive effect of ERT on survival in adults with Pompe disease. Given the relatively recent registration of ERT for Pompe disease, these findings further support its beneficial impact in adult patients.
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The heparanase/syndecan-1 axis in cancer: mechanisms and therapies.
FEBS J.
PUBLISHED: 01-25-2013
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Heparanase is an endoglucuronidase that cleaves heparan sulfate chains of proteoglycans. In many malignancies, high heparanase expression and activity correlate with an aggressive tumour phenotype. A major consequence of heparanase action in cancer is a robust up-regulation of growth factor expression and increased shedding of syndecan-1 (a transmembrane heparan sulfate proteoglycan). Substantial evidence indicates that heparanase and syndecan-1 work together to drive growth factor signalling and regulate cell behaviours that enhance tumour growth, dissemination, angiogenesis and osteolysis. Preclinical and clinical studies have demonstrated that therapies targeting the heparanase/syndecan-1 axis hold promise for blocking the aggressive behaviour of cancer.
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Involvement of heparanase in atherosclerosis and other vessel wall pathologies.
Matrix Biol.
PUBLISHED: 01-24-2013
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Heparanase, the sole mammalian endoglycosidase degrading heparan sulfate, is causally involved in cancer metastasis, angiogenesis, inflammation and kidney dysfunction. Despite the wide occurrence and impact of heparan sulfate proteoglycans in vascular biology, the significance of heparanase in vessel wall disorders is underestimated. Blood vessels are highly active structures whose morphology rapidly adapts to maintain vascular function under altered systemic and local conditions. In some pathologies (restenosis, thrombosis, atherosclerosis) this normally beneficial adaptation may be detrimental to overall function. Enzymatic dependent and independent effects of heparanase on arterial structure mechanics and repair closely regulate arterial compliance and neointimal proliferation following endovascular stenting. Additionally, heparanase promotes thrombosis after vascular injury and contributes to a pro-coagulant state in human carotid atherosclerosis. Importantly, heparanase is closely associated with development and progression of atherosclerotic plaques, including stable to unstable plaque transition. Consequently, heparanase levels are markedly increased in the plasma of patients with acute myocardial infarction. Noteworthy, heparanase activates macrophages, resulting in marked induction of cytokine expression associated with plaque progression towards vulnerability. Together, heparanase emerges as a regulator of vulnerable lesion development and potential target for therapeutic intervention in atherosclerosis and related vessel wall complications.
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Proteoglycans in cancer biology, tumour microenvironment and angiogenesis.
J. Cell. Mol. Med.
PUBLISHED: 12-13-2011
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Proteoglycans, key molecular effectors of cell surface and pericellular microenvironments, perform multiple functions in cancer and angiogenesis by virtue of their polyhedric nature and their ability to interact with both ligands and receptors that regulate neoplastic growth and neovascularization. Some proteoglycans such as perlecan, have pro- and anti-angiogenic activities, whereas other proteoglycans, such as syndecans and glypicans, can also directly affect cancer growth by modulating key signalling pathways. The bioactivity of these proteoglycans is further modulated by several classes of enzymes within the tumour microenvironment: (i) sheddases that cleave transmembrane or cell-associated syndecans and glypicans, (ii) various proteinases that cleave the protein core of pericellular proteoglycans and (iii) heparanases and endosulfatases which modify the structure and bioactivity of various heparan sulphate proteoglycans and their bound growth factors. In contrast, some of the small leucine-rich proteoglycans, such as decorin and lumican, act as tumour repressors by physically antagonizing receptor tyrosine kinases including the epidermal growth factor and the Met receptors or integrin receptors thereby evoking anti-survival and pro-apoptotic pathways. In this review we will critically assess the expanding repertoire of molecular interactions attributed to various proteoglycans and will discuss novel proteoglycan functions modulating cancer progression, invasion and metastasis and how these factors regulate the tumour microenvironment.
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Urinary F2-isoprostanes as a biomarker of reduced risk of type 2 diabetes.
Diabetes Care
PUBLISHED: 11-18-2011
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We have previously reported evidence of an inverse association between a urinary F(2)-isoprostane and type 2 diabetes risk in a pilot case-control study nested within the Insulin Resistance Atherosclerosis Study (IRAS). Here, we report the results from the study extended to the entire IRAS cohort.
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Nonoperative management of adult blunt splenic injury with and without splenic artery embolotherapy: a meta-analysis.
J Trauma
PUBLISHED: 10-12-2011
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Observation and splenic artery embolotherapy (SAE) are nonoperative management (NOM) modalities for adult blunt splenic injury; however, they are quite different, inconsistently applied, and controversial. This meta-analysis compares the known outcomes data for observational management versus SAE by splenic injury grade cohort.
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Urinary F2-isoprostanes, obesity, and weight gain in the IRAS cohort.
Obesity (Silver Spring)
PUBLISHED: 09-29-2011
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Obesity has been associated with increased F(2)-isoprostane (F(2)-IsoP) levels cross-sectionally. However, the prospective association may be inverse, based on our earlier finding that elevated urinary F(2)-IsoP levels predict lower risk of diabetes. This earlier finding led us to hypothesize that urinary F(2)-IsoPs reflect the intensity of oxidative metabolism and as such predict lower risk of both diabetes and weight gain. We examined cross-sectional relationships with obesity and prospective relationships with weight gain using the data from 299 participants of the Insulin Resistance Atherosclerosis Study (IRAS), all of whom were free of diabetes at baseline. Four urinary F(2)-IsoPs were assayed in stored baseline urine samples using liquid chromatography with tandem mass spectrometry: iPF(2?)-III, 2,3-dinor-iPF(2?)-III, iPF(2?)-VI, and 8,12-iso-iPF(2?)-VI (F(2)-IsoP 1-4, respectively). Baseline F(2)-IsoPs were positively associated with baseline measures of obesity; the strongest associations were found with two F(2)-IsoPs: odds ratios (95% confidence intervals) for overall and abdominal obesity were 1.74 (1.26-2.40) and 1.63 (1.18-2.24) for F(2)-IsoP2 and 1.47 (1.12-1.94) and 1.64 (1.22-2.20) for F(2)-IsoP4. F(2)-IsoP2 showed the strongest and significant inverse association with weight gain during the 5-year follow-up period: increase in F(2)-IsoP2 equal to 1 s.d. was associated with 0.90 kg lower weight gain (P = 0.02) and the odds ratios for relative (?5%) and absolute (?5 kg) weight gain were 0.67 (0.47-0.96) and 0.57 (0.37-0.87), respectively. The other three F(2)-IsoPs were consistently inversely associated with weight gain, although not significantly, suggesting that different F(2)-IsoPs vary in their ability to detect the association with weight gain.
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Parental intermittent claudication as risk factor for claudication in adults.
Am. J. Cardiol.
PUBLISHED: 09-14-2011
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Little is known about the familial aggregation of intermittent claudication (IC). Our objective was to examine whether parental IC increased the risk of IC in adult offspring, independent of the established cardiovascular risk factors. We evaluated the Offspring Cohort Participants of the Framingham Heart Study who were ?30 years old, cardiovascular disease free, and had both parents enrolled in the Framingham Heart Study (n = 2,970 unique participants, 53% women). Pooled proportional hazards regression analysis was used to examine whether the 12-year risk of incident IC in offspring participants was associated with parental IC, adjusting for age, gender, diabetes, smoking, systolic blood pressure, total cholesterol, high-density lipoprotein cholesterol, and antihypertensive and lipid treatment. Of the 909 person-examinations in the parental IC history group and 5,397 person-examinations in the no-parental IC history group, there were 101 incident IC events (29 with parental IC history and 72 without a parental IC history) during follow-up. The age- and gender-adjusted 12-year cumulative incidence rate per 1,000 person-years was 5.08 (95% confidence interval [CI] 2.74 to 7.33) and 2.34 (95% CI 1.46 to 3.19) in participants with and without a parental IC history. A parental history of IC significantly increased the risk of incident IC in the offspring (multivariable adjusted hazard ratio 1.81, 95% CI 1.14 to 2.88). The hazard ratio was unchanged, with an adjustment for the occurrence of cardiovascular disease (hazard ratio 1.83, 95% CI 1.15 to 2.91). In conclusion, IC in parents increases the risk of IC in adult offspring, independent of the established risk factors. These data suggest a genetic component of peripheral artery disease and support future research into genetic causes.
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Common carotid artery intima-media thickness progression as a predictor of stroke in multi-ethnic study of atherosclerosis.
Stroke
PUBLISHED: 09-01-2011
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Carotid artery intima-media thickness (IMT) is a marker of cardiovascular disease associated with incident stroke. We studied whether IMT rate of change is associated with stroke.
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Carotid-wall intima-media thickness and cardiovascular events.
N. Engl. J. Med.
PUBLISHED: 07-22-2011
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Intima-media thickness of the walls of the common carotid artery and internal carotid artery may add to the Framingham risk score for predicting cardiovascular events.
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Assessment of genetic determinants of the association of ? fibrinogen in relation to cardiovascular disease.
Arterioscler. Thromb. Vasc. Biol.
PUBLISHED: 07-14-2011
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? fibrinogen is a newly emerging biomarker that is associated with cardiovascular disease (CVD). However, the genetic determinants of ? fibrinogen levels are unknown. We therefore conducted a genome-wide association study on 3042 participants from the Framingham Heart Study Offspring Cohort.
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In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.