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Perspective: The RNA exosome, cytokine gene regulation and links to autoimmunity

Tue, 06/14/2016 - 10:42am

The RNA exosome is a highly conserved exoribonuclease complex that is involved in RNA processing, quality control and turnover regulation. The exosome plays pleiotropic functions by recruiting different cofactors that regulate its target specificity. Recently, the exosome has been implicated in the regulation of immune processes including cytokine production and negative regulation of innate sensing of nucleic acids. Careful regulation of such mechanisms is critical to avoid a breakdown of self-tolerance and the pathogenesis of autoimmune disorders. This perspective briefly introduces the exosome, its its normal function in RNA biology and summarizes regulatory roles of the RNA exosome in immunity. Finally we discuss how dysregulation of exosome function can lead to autoimmune disease.

Management of axilla in breast cancer - The saga continues

Tue, 06/14/2016 - 10:42am

Prospective trials investigating the accuracy of SLNB for cN0 (primary surgical therapy) and cN1 patients (neoadjuvant chemotherapy) have not utilized likelihood ratios (LR) to assess the impact of false negative SLNB. This review evaluates the evidence on accuracy of SLNB using STARD and QUADAS-2 (revised) criteria for patients undergoing primary surgical therapy and primary chemotherapy. It utilizes the: (i) Reported rates for pre-test probabilities of node positive disease from Surveillance, Epidemiology, and End Results (SEER) database for the cN0 patients (primary surgical therapy) for each T stage; calculates the negative LR from cumulative evidence; and uses the Bayesian nomogram to compute the post-test probability of missing the metastatic axillary node based on negative SLNB. (ii) Reported rates of complete axillary response in ACOSOG-Z1071 trial for cN1 patients to calculate the pre-test probabilities of residual nodal disease for each biological tumor sub-type; calculates the negative LR from ACOSOG-Z1071, and SENTINA trial data; and uses the Bayesian nomogram to compute the post-test probability of missing the residual metastatic axillary node based on negative SLNB. For cN0 disease, the odds of missing axillary disease based on negative SLNB for each T stage are: T1a = 0.7%; T1b = 1.5%; T1c = 3%; T2 = 7%; T3 = 18%. For cN1 disease, the odds of missing residual axillary disease based on negative SLNB for each biological subtype are: HER2neu+ = 8%; Triple negative = 15%; ER+/PR+/HER2neu- = 45%. Negative LR is more accurate and superior to false negative rate for determining the clinical utility of SLNB by taking into account the changing pre-test probability of disease.

The increased use of computed tomography angiography and magnetic resonance angiography as the sole imaging modalities prior to infrainguinal bypass has had no effect on outcomes

Tue, 06/14/2016 - 10:41am

BACKGROUND: Angiography remains the gold standard imaging modality before infrainguinal bypass. Computed tomography angiography (CTA) and magnetic resonance angiography (MRA) have emerged as noninvasive alternatives for preoperative imaging. We sought to examine contemporary trends in the utilization of CTA and MRA as isolated imaging modalities before infrainguinal bypass and to compare outcomes following infrainguinal bypass in patients who underwent CTA or MRA versus those who underwent conventional arteriography.

METHODS: Patients undergoing infrainguinal bypass within the Vascular Study Group of New England were identified (2003-2012). Patients were stratified by preoperative imaging modality: CTA/MRA alone or conventional angiography. Trends in utilization of these modalities were examined and demographics of these groups were compared. Primary end points included primary patency, secondary patency, and major adverse limb events (MALE) at 1 year as determined by Kaplan-Meier analysis. Multivariable Cox proportional hazards models were constructed to evaluate the effect of imaging modality on primary patency, secondary patency, and MALE after adjusting for confounders.

RESULTS: In 3123 infrainguinal bypasses, CTA/MRA alone was used in 462 cases (15%) and angiography was used in 2661 cases (85%). Use of CTA/MRA alone increased over time, with 52 (11%) bypasses performed between 2003 and 2005, 189 (41%) bypasses performed between 2006 and 2009, and 221 (48%) bypasses performed between 2010 and 2012 (P < 0.001). Patients with CTA/MRA alone, compared with patients with angiography, more frequently underwent bypass for claudication (33% vs. 26%, P = 0.001) or acute limb ischemia (13% vs. 5%, P < 0.0001), more frequently had prosthetic conduits (39% vs. 30%, P = 0.001), and less frequently had tibial/pedal targets (32% vs. 40%, P = 0.002). After adjusting for these and other confounders, multivariable analysis demonstrated that the use of CTA/MRA alone was not associated with a significant difference in 1 year primary patency (hazard ratio [HR] 0.95, 95% confidence interval [CI] 0.78-1.16), secondary patency (HR 1.30, 95% CI 0.99-1.72), or MALE (HR 1.08, 95% CI 0.89-1.32).

CONCLUSIONS: CTA and MRA are being increasingly used as the sole preoperative imaging modality before infrainguinal bypass. This shift in practice patterns appears to have no measurable effect on outcomes at 1 year.

Achieving the Triple Aim: A Curriculum Framework for Health Professions Education

Tue, 06/14/2016 - 10:40am

The 2014 Clinical Prevention and Population Health Curriculum Framework in this issue of the American Journal of Preventive Medicine is described as a resource for preparing health professionals to achieve the Triple Aim: improving the patient experience of care, reducing the per capita cost of care, and improving the health of the population. The strengths of the Framework in guiding health professions education are described and the consensus-based process that included members from major health professional organizations to develop the Framework is discussed. Links are provided to examples illustrating the Framework’s use in health professions educational settings.

The '16-hour rule': a giant step, but in which direction

Tue, 06/14/2016 - 10:40am

The purpose of our study is to examine postgraduate year PGY-1 resident perceptions of educational and patient care experiences in the medical intensive care unit (MICU) through a survey of 2 groups completing a first year of training before and after the 16-hour rule change.

Identification of Obesity and Cardiovascular Risk in Ethnically and Racially Diverse Populations: A Scientific Statement From the American Heart Association

Tue, 06/14/2016 - 10:40am

The purpose of this scientific statement is to describe the limitations of current simple measures, such as the use of BMI with standard thresholds to identify overweight and obesity, as applied to racial and ethnic minorities. The statement also addresses potential alternatives, as well as the diagnosis of obesity based on multiple risk factors, including race and ethnicity. On the basis of our extensive, systematic review of current literature and in collaboration with the American Heart Association’s (AHA) Obesity Committee of the Council on Lifestyle and Cardiometabolic Health, we have also made some key recommendations for clinical practice, research, and public health for improved identification of obesity and cardiovascular risks in a racially and ethnically diverse population.

Efficacy and safety results from a Phase 3, randomized, placebo-controlled trial of subcutaneous golimumab in Chinese patients with active rheumatoid arthritis despite methotrexate therapy

Tue, 06/14/2016 - 10:39am

AIM: The efficacy and safety of golimumab + methotrexate (MTX) were evaluated in Chinese patients with active rheumatoid arthritis (RA) despite MTX therapy.

METHODS: Chinese patients (n = 264) were randomly assigned (1 : 1) to receive subcutaneous injections of placebo + MTX with crossover to golimumab 50 mg + MTX at week 24 (Group 1) or to golimumab 50 mg + MTX (Group 2) every 4 weeks. Group 1 patients with inadequate response entered blinded early escape to golimumab 50 mg + MTX at week 16. At least a 20% improvement in the American College of Rheumatology (ACR20) criteria at week 14 was the primary endpoint. Other assessments included the 28-joint count Disease Activity Score using C-reactive protein (DAS28-CRP) and Health Assessment Questionnaire-Disability Index (HAQ-DI) through week 52. Adverse events (AEs) were monitored through week 56.

RESULTS: ACR20 response at week 14 was significantly higher in Group 2 (40.9% [54/132]) compared with Group 1 (15.9% [21/132]; P < 0.001). Greater proportions of patients in Group 2 compared with Group 1 had a DAS28-CRP response at week 14 (65.2% vs. 30.3%, P < 0.001) or ACR20 response at week 24 (42.4% vs. 15.9%, P < 0.001), and Group 2 had a significantly greater change in HAQ-DI at week 24 (-0.26 vs. 0.15, P < 0.001). After week 24, the proportion of patients achieving ACR20 in Group 1 approached that in Group 2. Through week 16, 23.5% of Group 1 and 26.7% of Group 2 patients reported AEs. Among golimumab + MTX-treated patients, 50.2% and 4.2% had > /= 1 AE or serious AE, respectively, through week 56. No unexpected safety signals were observed.

CONCLUSION: Among MTX-experienced Chinese patients with active RA, a significantly greater proportion of patients receiving golimumab + MTX had improvements in the signs and symptoms of RA compared with MTX monotherapy. Safety findings were consistent with previous studies of golimumab in patients with RA.

Cutting Edge: A Natural Antisense Transcript, AS-IL1alpha, Controls Inducible Transcription of the Proinflammatory Cytokine IL-1alpha

Tue, 06/14/2016 - 10:38am

Natural antisense transcripts (NATs) are a class of long noncoding RNAs (lncRNAs) that are complementary to other protein-coding genes. Although thousands of NATs are encoded by mammalian genomes, their functions in innate immunity are unknown. In this study, we identified and characterized a novel NAT, AS-IL1alpha, which is partially complementary to IL-1alpha. Similar to IL-1alpha, AS-IL1alpha is expressed at low levels in resting macrophages and is induced following infection with Listeria monocytogenes or stimulation with TLR ligands (Pam3CSK4, LPS, polyinosinic-polycytidylic acid). Inducible expression of IL-1alpha mRNA and protein were significantly reduced in macrophages expressing shRNA that target AS-IL1alpha. AS-IL1alpha is located in the nucleus and did not alter the stability of IL-1alpha mRNA. Instead, AS-IL1alpha was required for the recruitment of RNA polymerase II to the IL-1alpha promoter. In summary, our studies identify AS-IL1alpha as an important regulator of IL-1alpha transcription during the innate immune response.

Relationship Between Cerebrovascular Risk, Cognition, and Treatment Outcome in Late-Life Psychotic Depression

Tue, 06/14/2016 - 10:37am

OBJECTIVE: To examine whether cerebrovascular risk, executive function, and processing speed are associated with acute treatment outcome of psychotic depression in older adults.

METHODS: The authors analyzed data from 142 persons aged 60 years or older with major depression with psychotic features who participated in a 12-week randomized controlled trial (RCT) comparing olanzapine plus sertraline with olanzapine plus placebo. The independent variables were baseline cerebrovascular risk (Framingham Stroke Risk Score), baseline executive function (Stroop interference score and the initiation/perseveration subscale of the Mattis Dementia Rating Scale), and baseline processing speed (color and word reading components of the Stroop). The outcome variable was change in severity of depression, measured by the 17-item Hamilton Depression Rating Scale total score, during the course of the RCT.

RESULTS: Greater baseline cerebrovascular risk was significantly associated with less improvement in depression severity over time, after controlling for pertinent covariates. Neither executive function nor processing speed predicted outcome.

CONCLUSION: This study suggests an association of cerebrovascular risk, but not executive function or processing speed, with treatment outcome of major depression with psychotic features in older adults.

Quality indicators in rheumatoid arthritis: results from the METEOR database

Tue, 06/14/2016 - 10:37am

OBJECTIVE: To test the feasibility of collecting, storing, retrieving and analysing necessary information to fulfil a preliminary set of quality indicators (QIs) that have been proposed by an international task force in a large multinational clinical practice database of patients with RA.

METHODS: Data from all 12 487 patients with 46 005 visits in the Measurement of Efficacy of Treatment in the Era of Outcome in Rheumatology database from January 2008 until January 2012 were analysed to test the feasibility of collecting information on 10 QIs: time to diagnosis; frequency of visits; assessment of autoantibodies and radiographs, disease activity and function; disease remission, low disease activity, normal function; time to first DMARD and type of first DMARD. For each QI, two aspects were assessed: information availability and target achievement.

RESULTS: Information was available for < 50% of patients regarding the following QIs: time to diagnosis, assessment of ACPAs or radiographs, time to first DMARD and type of first DMARD. Information was available for function assessment in 49% of visits and 67% of patients and for disease activity assessment in 85% of visits and 86% of patients. Information relevant to the QI frequency of visits was available for all patients. Relevant information to calculate the proportion of patients who achieved a defined target could be obtained for all QIs.

CONCLUSION: Collecting storing, retrieving and analysing the core data necessary to meaningfully assess quality of care is feasible in a multinational, practice-based electronic database.

Smoking Status and Pain Intensity Among OEF/OIF/OND Veterans

Tue, 06/14/2016 - 10:36am

OBJECTIVE: Pain and smoking are highly prevalent among Veterans. Studies in non-Veteran populations have reported higher pain intensity among current smokers compared with nonsmokers and former smokers. We examined the association of smoking status with reported pain intensity among Veterans of Operations Enduring Freedom, Iraqi Freedom, and New Dawn (OEF/OIF/OND).

DESIGN: The sample consisted of OEF/OIF/OND Veterans who had at least one visit to Veterans Affairs (2001-2012) with information in the electronic medical record for concurrent smoking status and pain intensity. The primary outcome measure was current pain intensity, categorized as none to mild (0-3); moderate (4-6); or severe ( > /=7); based on a self-reported 11-point pain numerical rating scale. Multivariable logistic regression analyses were used to assess the association of current smoking status with moderate to severe ( > /=4) pain intensity, controlling for potential confounders.

RESULTS: Overall, 50,988 women and 355,966 men Veterans were examined. The sample mean age was 30 years; 66.3% reported none to mild pain; 19.8% moderate pain; and 13.9% severe pain; 37% were current smokers and 16% former smokers. Results indicated that current smoking [odds ratio (OR) = 1.29 (95% confidence intervals (CI) = 1.27-1.31)] and former smoking [OR = 1.02 (95% CI = 1.01-1.05)] were associated with moderate to severe pain intensity, controlling for age, service-connected disability, gender, obesity, substance abuse, mood disorders, and Post Traumatic Stress Disorder.

CONCLUSIONS: We found an association between current smoking and pain intensity. This effect was attenuated in former smokers. Our study highlights the importance of understanding reported pain intensity in OEF/OIF/OND Veterans who continue to smoke.

Determinants of survival and major amputation after peripheral endovascular intervention for critical limb ischemia

Tue, 06/14/2016 - 10:36am

OBJECTIVE: Our objective was to analyze periprocedural and 1-year outcomes of peripheral endovascular intervention (PVI) for critical limb ischemia (CLI).

METHODS: We reviewed 1244 patients undergoing 1414 PVIs for CLI (rest pain, 29%; tissue loss, 71%) within the Vascular Study Group of New England (VSGNE) from January 2010 to December 2011. Overall survival (OS), amputation-free survival (AFS), and freedom from major amputation at 1 year were analyzed using the Kaplan-Meier method. Cox proportional hazards models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs).

RESULTS: The number of arteries treated during each procedure were 1 (49%), 2 (35%), 3 (12%), and > /=4 (5%). Target arterial segments and TransAtlantic Inter-Society Consensus classifications were aortoiliac, 27% (A, 48%; B, 28%; C, 12%; and D, 12%); femoral-popliteal, 48% (A, 29%; B, 34%; C, 20%; and D, 17%); and infrapopliteal, 25% (A, 17%; B, 14%; C, 25%; D, 44%). Technical success was 92%. Complications included access site hematoma (5.0%), occlusion (0.3%), and distal embolization (2.4%). Mortality and major amputation rates were 2.8% and 2.2% at 30 days, respectively. Overall percutaneous or open reintervention rate was 8.0% during the first year. At 1-year, OS, AFS, and freedom from major amputation were 87%, 87%, and 94% for patients with rest pain and 80%, 71%, and 81% for patients with tissue loss. Independent predictors of reduced 1-year OS (C index = .74) included dialysis (HR, 3.8; 95% CI, 2.8-5.1; P < .01), emergency procedure (HR, 2.5; 95% CI, 1.0-6.2; P = .05), age > 80 years (HR, 2.2; 95% CI, 1.7-2.8; P < .01), not living at home preoperatively (HR, 2.0; 95% CI, 1.4-2.8; P < .01), creatinine > 1.8 mg/dL (HR, 1.9; 95% CI, 1.3-2.8; P < .01), congestive heart failure (HR, 1.7; 95% CI, 1.3-2.2; P < .01), and chronic beta-blocker use (HR, 1.4; 95% CI, 1.0-1.9; P = .03), whereas independent preoperative ambulation (HR, 0.7; 95% CI, 0.6-0.9; P = .014) was protective. Independent predictors of major amputation (C index = .69) at 1 year included dialysis (HR, 2.7; 95% CI, 1.6-4.5; P < .01), tissue loss (HR, 2.0; 95% CI, 1.1-3.7; P = .02), prior major contralateral amputation (HR, 2.0; 95% CI, 1.1-3.5; P = .02), non-Caucasian race (HR, 1.7; 95% CI, 1.0-2.9; P = .045), and male gender (HR, 1.6; 95% CI, 1.1-2.6; P = .03), whereas smoking (HR, .60; 95% CI, 0.4-1.0; P = .042) was protective.

CONCLUSIONS: Survival and major amputation after PVI for CLI are associated with different patient characteristics. Dialysis dependence is a common predictor that portends especially poor outcomes. These data may facilitate efforts to improve patient selection and, after further validation, enable risk-adjusted outcome reporting for CLI patients undergoing PVI.

Development and psychometric properties of the family distress in advanced dementia scale

Tue, 06/14/2016 - 10:35am

OBJECTIVE: The majority of scales to measure family member distress in dementia are designed for community settings and do not capture the unique burdens of the nursing home (NH) environment. We report the psychometric properties of a new Family Distress in Advanced Dementia Scale for use in the NH setting.

DESIGN, SETTING, PARTICIPANTS: Cross-sectional questionnaire of 130 family member health care proxies of NH residents with advanced dementia in 31 Boston-area NHs.

METHODS: Thirty-one initial items were evaluated, measuring the frequency over the past 3 months of sources of distress. Exploratory factor analysis identified domains of distress; Cronbach's alpha was computed for each domain. Associations between the domains and other measures were evaluated using Pearson correlation coefficients, including measures of depression (PHQ-9), satisfaction with care (Satisfaction with Care at the End-of-Life in Dementia [SWC-EOLD]), and caregiver burden (Zarit Burden Interview short version).

RESULTS: Factor analysis suggested 3 domains: emotional distress (9 items), dementia preparedness (5 items), and NH relations (7 items). Cronbach's alpha coefficients were 0.82, 0.75, and 0.83 respectively. The PHQ-9 correlated most strongly with the emotional distress factor (r = 0.34), the SWC-EOWD correlated most strongly with the NH relations factor (r = 0.35), as did the Zarit Burden Scale (r = 0.50).

CONCLUSIONS: The Family Distress in Advanced Dementia Scale encompasses 3 domains of distress. This scale represents a much needed tool to assess distress among family members of NH residents with advanced dementia and provides a metric to evaluate interventions in the population.

Inflammasome activation in the liver: Focus on alcoholic and non-alcoholic steatohepatitis

Tue, 06/14/2016 - 10:35am

Upregulation of the inflammatory cascade is a major element both in the progression of steatohepatitis to severe alcoholic hepatitis as well as in the progression of NASH to advanced NASH with fibrosis. The mechanisms underpinning these changes are only partially understood. Activation of the inflammatory cascade requires multiple stimuli and in this report, we discuss the role of inflammasomes that activate IL-1beta as well as the sterile and pathogen-derived danger signals that results in inflammasome activation and inflammation in alcoholic and non-alcoholic steatohepatitis. The dynamics of inflammasome activation, the cell types involved and the trigger signals appear to be somewhat different between ASH and NASH. Further studies are needed to dissect the pathology-related differences between these two major forms of steatohepatitis. Clinical and therapeutic implications of inflammasome activation in steatohepatitis are also discussed.

Juvenile Justice, Mental Health, and the Transition to Adulthood: A Review of Service System Involvement and Unmet Needs in the U.S

Tue, 06/14/2016 - 10:34am

Although adolescents are the primary focus of juvenile justice, a significant number of young people involved with this system are considered transition age youth (i.e., 16-25 years of age). The aim of this review is to summarize the specific needs of transition age youth with mental health conditions involved with the juvenile justice system, identify the multiple service systems relevant to this group, and offer recommendations for policies and practice. A comprehensive search strategy was used to identify and synthesize the literature. Findings highlight the paucity of research specific to transition age youth. Thus, we also summarized relevant research on justice-involved adolescents, with a focus evaluating its potential relevance in the context of the unique milestones of the transition age, including finishing one's education, setting and working towards vocational goals, and transitioning from ones' family of origin to more independent living situations. Existing programs and initiatives relevant to transition age youth with mental health conditions are highlighted, and nine specific recommendations for policy and practice are offered.

Effect of Delirium and Other Major Complications on Outcomes After Elective Surgery in Older Adults

Tue, 06/14/2016 - 10:33am

IMPORTANCE: Major postoperative complications and delirium contribute independently to adverse outcomes and high resource use in patients who undergo major surgery; however, their interrelationship is not well examined.

OBJECTIVE: To evaluate the association of major postoperative complications and delirium, alone and combined, with adverse outcomes after surgery.

DESIGN, SETTING, AND PARTICIPANTS: Prospective cohort study in 2 large academic medical centers of 566 patients who were 70 years or older without recognized dementia or a history of delirium and underwent elective major orthopedic, vascular, or abdominal surgical procedures with a minimum 3-day hospitalization between June 18, 2010, and August 8, 2013. Data analysis took place from December 13, 2013, through May 1, 2015.

MAIN OUTCOMES AND MEASURES: Major postoperative complications, defined as life-altering or life-threatening events (Accordion Severity grade 2 or higher), were identified by expert-panel adjudication. Delirium was measured daily with the Confusion Assessment Method and a validated medical record review method. The following 4 subgroups were analyzed: (1) no complications or delirium; (2) complications only; (3) delirium only; and (4) complications and delirium. Adverse outcomes included a length of stay (LOS) of more than 5 days, institutional discharge, and rehospitalization within 30 days of discharge.

RESULTS: In the 566 participants, the mean (SD) age was 76.7 (5.2) years, 236 (41.7%) were male, and 523 (92.4%) were white. Forty-seven patients (8.3%) developed major complications and 135 (23.9%) developed delirium. Compared with no complications or delirium as the reference group, major complications only contributed to prolonged LOS only (relative risk [RR], 2.8; 95% CI, 1.9-4.0); by contrast, delirium only significantly increased all adverse outcomes, including prolonged LOS (RR, 1.9; 95% CI, 1.4-2.7), institutional discharge (RR, 1.5; 95% CI, 1.3-1.7), and 30-day readmission (RR, 2.3; 95% CI, 1.4-3.7). The subgroup with complications and delirium had the highest rates of all adverse outcomes, including prolonged LOS (RR, 3.4; 95% CI, 2.3-4.8), institutional discharge (RR, 1.8; 95% CI, 1.4-2.5), and 30-day readmission (RR, 3.0; 95% CI, 1.3-6.8). Delirium exerted the highest attributable risk at the population level (5.8%; 95% CI, 4.7-6.8) compared with all other adverse events (prolonged LOS, institutional discharge, or readmission).

CONCLUSIONS AND RELEVANCE: Major postoperative complications and delirium are separately associated with adverse events and demonstrate a combined effect. Delirium occurs more frequently and has a greater effect at the population level than other major complications.

Characterization of the platelet transcriptome by RNA sequencing in patients with acute myocardial infarction

Tue, 06/14/2016 - 10:33am

Transcripts in platelets are largely produced in precursor megakaryocytes but remain physiologically active as platelets translate RNAs and regulate protein/RNA levels. Recent studies using transcriptome sequencing (RNA-seq) characterized the platelet transcriptome in limited number of non-diseased individuals. Here, we expand upon these RNA-seq studies by completing RNA-seq in platelets from 32 patients with acute myocardial infarction (MI). Our goals were to characterize the platelet transcriptome using a population of patients with acute MI and relate gene expression to platelet aggregation measures and ST-segment elevation MI (STEMI) (n = 16) vs. non-STEMI (NSTEMI) (n = 16) subtypes. Similar to other studies, we detected 9565 expressed transcripts, including several known platelet-enriched markers (e.g. PPBP, OST4). Our RNA-seq data strongly correlated with independently ascertained platelet expression data and showed enrichment for platelet-related pathways (e.g. wound response, hemostasis, and platelet activation), as well as actin-related and post-transcriptional processes. Several transcripts displayed suggestively higher (FBXL4, ECHDC3, KCNE1, TAOK2, AURKB, ERG, and FKBP5) and lower (MIAT, PVRL3, and PZP) expression in STEMI platelets compared to NSTEMI. We also identified transcripts correlated with platelet aggregation to TRAP (ATP6V1G2, SLC2A3), collagen (CEACAM1, ITGA2), and ADP (PDGFB, PDGFC, ST3GAL6). Our study adds to current platelet gene expression resources by providing transcriptome-wide analyses in platelets isolated from patients with acute MI. In concert with prior studies, we identify various genes for further study in regards to platelet function and acute MI. Future platelet RNA-seq studies examining more diverse sets of healthy and diseased samples will add to our understanding of platelet thrombotic and non-thrombotic functions.

Construct validation of the dietary inflammatory index among postmenopausal women

Thu, 06/09/2016 - 12:10pm

PURPOSE: Many dietary factors have either proinflammatory or anti-inflammatory properties. We previously developed a dietary inflammatory index (DII) to assess the inflammatory potential of diet. In this study, we conducted a construct validation of the DII based on data from a food frequency questionnaire and three inflammatory biomarkers in a subsample of 2567 postmenopausal women in the Women's Health Initiative Observational Study.

METHODS: We used multiple linear and logistic regression models, controlling for potential confounders, to test whether baseline DII predicted concentrations of interleukin-6, high-sensitivity C-reactive protein (hs-CRP), tumor necrosis factor alpha receptor 2, or an overall biomarker score combining all three inflammatory biomarkers.

RESULTS: The DII was associated with the four biomarkers with beta estimates (95% confidence interval) comparing the highest with lowest DII quintiles as follows: interleukin-6: 1.26 (1.15-1.38), Ptrend < .0001; tumor necrosis factor alpha receptor 2: 81.43 (19.15-143.71), Ptrend = .004; dichotomized hs-CRP (odds ratio for higher vs. lower hs-CRP): 1.30 (0.97-1.67), Ptrend = .34; and the combined inflammatory biomarker score: 0.26 (0.12-0.40), Ptrend = .0001.

CONCLUSIONS: The DII was significantly associated with inflammatory biomarkers. Construct validity of the DII indicates its utility for assessing the inflammatory potential of diet and for expanding its use to include associations with common chronic diseases in future studies.

Semiparametric time to event models in the presence of error-prone, self-reported outcomes - with application to the Women's Health Initiative

Thu, 06/09/2016 - 12:10pm

The onset of several silent, chronic diseases such as diabetes can be detected only through diagnostic tests. Due to cost considerations, self-reported outcomes are routinely collected in lieu of expensive diagnostic tests in large-scale prospective investigations such as the Women's Health Initiative. However, self-reported outcomes are subject to imperfect sensitivity and specificity. Using a semiparametric likelihood-based approach, we present time to event models to estimate the association of one or more covariates with a error-prone, self-reported outcome. We present simulation studies to assess the effect of error in self-reported outcomes with regard to bias in the estimation of the regression parameter of interest. We apply the proposed methods to prospective data from 152,830 women enrolled in the Women's Health Initiative to evaluate the effect of statin use with the risk of incident diabetes mellitus among postmenopausal women. The current analysis is based on follow-up through 2010, with a median duration of follow-up of 12.1 years. The methods proposed in this paper are readily implemented using our freely available R software package icensmis, which is available at the Comprehensive R Archive Network (CRAN) website.

Inflammatory potential of diet and all-cause, cardiovascular, and cancer mortality in National Health and Nutrition Examination Survey III Study

Thu, 06/09/2016 - 12:09pm

BACKGROUND: Various dietary components have been studied in relation to overall mortality; however, little is known about the relationship between the inflammatory potential of overall diet and mortality.

MATERIALS AND METHODS: We examined the association between the dietary inflammatory index (DII) and mortality in the National Health and Nutrition Examination Survey III follow-up study. The DII was computed from baseline dietary intake assessed using 24-h dietary recalls (1988-1994). Mortality was determined from the National Death Index records through 2006. Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95 % confidence interval (95 % CI). During the follow-up, 2795 deaths were identified, including 1233 due to cardiovascular disease (CVD), and 615 due to cancer, 158 of which were due to digestive-tract cancers.

RESULTS: Multivariate Cox proportional hazards regression analyses, adjusting for age, race, diabetes status, hypertension, physical activity, body mass index, poverty index, and smoking, revealed positive associations between higher DII scores and mortality. Comparing subjects in DII tertile 3 versus tertile 1, significant associations were noted for all-cause mortality (HRTertile3vs1 1.34; 95 % CI 1.19-1.51, P trend < 0.0001), CVD mortality (HRTertile3vs1 1.46; 95 % CI 1.18-1.81, P trend = 0.0006), cancer mortality (HRTertile3vs1 1.46; 95 % CI 1.10-1.96, P trend = 0.01), and digestive-tract cancer mortality (HRTertile3vs1 2.10; 95 % CI 1.15-3.84, P trend = 0.03).

CONCLUSION: These results indicate that a pro-inflammatory diet, as indicated by higher DII scores, was associated with higher risk of all-cause, CVD, and cancer mortality.