Restrictive or Liberal Transfusion Strategy in Myocardial Infarction and Anemia.

BACKGROUND: A strategy of administering a transfusion only when the hemoglobin level falls below 7 or 8 g per deciliter has been widely adopted. However, patients with acute myocardial infarction may benefit from a higher hemoglobin level. METHODS: In this phase 3, interventional trial, we randomly assigned patients with myocardial infarction and a hemoglobin level of less than 10 g per deciliter to a restrictive transfusion strategy (hemoglobin cutoff for transfusion, 7 or 8 g per deciliter) or a liberal transfusion strategy (hemoglobin cutoff, <10 g per deciliter). The primary outcome was a composite of myocardial infarction or death at 30 days. RESULTS: A total of 3504 patients were included in the primary analysis. The mean (±SD) number of red-cell units that were transfused was 0.7±1.6 in the restrictive-strategy group and 2.5±2.3 in the liberal-strategy group. The mean hemoglobin level was 1.3 to 1.6 g per deciliter lower in the restrictive-strategy group than in the liberal-strategy group on days 1 to 3 after randomization. A primary-outcome event occurred in 295 of 1749 patients (16.9%) in the restrictive-strategy group and in 255 of 1755 patients (14.5%) in the liberal-strategy group (risk ratio modeled with multiple imputation for incomplete follow-up, 1.15; 95% confidence interval [CI], 0.99 to 1.34; P = 0.07). Death occurred in 9.9% of the patients with the restrictive strategy and in 8.3% of the patients with the liberal strategy (risk ratio, 1.19; 95% CI, 0.96 to 1.47); myocardial infarction occurred in 8.5% and 7.2% of the patients, respectively (risk ratio, 1.19; 95% CI, 0.94 to 1.49). CONCLUSIONS: In patients with acute myocardial infarction and anemia, a liberal transfusion strategy did not significantly reduce the risk of recurrent myocardial infarction or death at 30 days. However, potential harms of a restrictive transfusion strategy cannot be excluded. (Funded by the National Heart, Lung, and Blood Institute and others; MINT ClinicalTrials.gov number, NCT02981407.).

Rationale and design for the myocardial ischemia and transfusion (MINT) randomized clinical trial.

BACKGROUND: Accumulating evidence from clinical trials suggests that a lower (restrictive) hemoglobin threshold (<8 g/dL) for red blood cell (RBC) transfusion, compared with a higher (liberal) threshold (≥10 g/dL) is safe. However, in anemic patients with acute myocardial infarction (MI), maintaining a higher hemoglobin level may increase oxygen delivery to vulnerable myocardium resulting in improved clinical outcomes. Conversely, RBC transfusion may result in increased blood viscosity, vascular inflammation, and reduction in available nitric oxide resulting in worse clinical outcomes. We hypothesize that a liberal transfusion strategy would improve clinical outcomes as compared to a more restrictive strategy. METHODS: We will enroll 3500 patients with acute MI (type 1, 2, 4b or 4c) as defined by the Third Universal Definition of MI and a hemoglobin <10 g/dL at 144 centers in the United States, Canada, France, Brazil, New Zealand, and Australia. We randomly assign trial participants to a liberal or restrictive transfusion strategy. Participants assigned to the liberal strategy receive transfusion of RBCs sufficient to raise their hemoglobin to at least 10 g/dL. Participants assigned to the restrictive strategy are permitted to receive transfusion of RBCs if the hemoglobin falls below 8 g/dL or for persistent angina despite medical therapy. We will contact each participant at 30 days to assess clinical outcomes and at 180 days to ascertain vital status. The primary end point is a composite of all-cause death or recurrent MI through 30 days following randomization. Secondary end points include all-cause mortality at 30 days, recurrent adjudicated MI, and the composite outcome of all-cause mortality, nonfatal recurrent MI, ischemia driven unscheduled coronary revascularization (percutaneous coronary intervention or coronary artery bypass grafting), or readmission to the hospital for ischemic cardiac diagnosis within 30 days. The trial will assess multiple tertiary end points. CONCLUSIONS: The MINT trial will inform RBC transfusion practice in patients with acute MI.

HDL (High-Density Lipoprotein) Subclasses, Lipid Content, and Function Trajectories Across the Menopause Transition: SWAN-HDL Study.

OBJECTIVE: The cardioprotective capacity of HDL (high-density lipoprotein) cholesterol postmenopause has been challenged. HDL subclasses, lipid contents, and function might be better predictors of cardiovascular risk than HDL cholesterol. Changes in these measures have not been characterized over the menopause transition (MT) with respect to timing relative to the final menstrual period. Approach and Results: Four hundred seventy-one women with HDL particle (HDL-P) subclasses (nuclear magnetic resonance spectroscopy total, large, medium, and small HDL-P and HDL size), HDL lipid content (HDL phospholipids and triglycerides), and HDL function (cholesterol efflux capacity [HDL-CEC]) measured for a maximum of 5 time points across the MT were included. HDL cholesterol and total HDL-P increased across the MT. Within the 1 to 2 years bracketing the final menstrual period, large HDL-P and HDL size declined while small HDL-P and HDL-triglyceride increased. Although overall HDL-CEC increased across the MT, HDL-CEC per HDL-P declined. Higher concentrations of total, large, and medium HDL-P and greater HDL size were associated with greater HDL-CEC while of small HDL-P were associated with lower HDL-CEC. Associations of large HDL-P and HDL size with HDL-CEC varied significantly across the MT such that higher large HDL-P concentrations and greater HDL size were associated with lower HDL-CEC within the 1 to 2 years around the final menstrual period. CONCLUSIONS: Although HDL cholesterol increased over the MT, HDL subclasses and lipid content showed adverse changes. While overall HDL-CEC increased, HDL-CEC per HDL-P declined, consistent with reduced function per particle. Large HDL-P may become less efficient in promoting HDL-CEC during the MT.

Plasma trial: Pilot randomized clinical trial to determine safety and efficacy of plasma transfusions.

BACKGROUND: Plasma is frequently administered to patients with prolonged INR prior to invasive procedures. However, there is limited evidence evaluating efficacy and safety. STUDY DESIGN AND METHODS: We performed a pilot trial in hospitalized patients with INR between 1.5 and 2.5 undergoing procedures conducted outside the operating room. We excluded patients undergoing procedures proximal to the central nervous system, platelet counts <40,000/µl, or congenital or acquired coagulation disorders unresponsive to plasma. We randomly allocated patients stratified by hospital and history of cirrhosis to receive plasma transfusion (10-15 cc/kg) or no transfusion. The primary outcome was change in hemoglobin concentration within 2 days of procedure. RESULTS: We enrolled 57 patients, mean age 56.0, 34 (59.6%) with cirrhosis, and mean INR 1.92 (SD = 0.27). In the intention to treat analysis, there were 10 of 27 (38.5%) participants in the plasma arm with a post procedure INR <1.5 and one of 30 (3.6%) in the no treatment arm (p < .01). The mean INR after receiving plasma transfusion was -0.24 (SD 0.26) lower than baseline. The change from pre-procedure hemoglobin level to lowest level within 2 days was -0.6 (SD = 1.0) in the plasma transfusion arm and -0.4 (SD = 0.6) in the no transfusion arm (p = .29). Adverse outcomes were uncommon. DISCUSSION: We found no differences in change in hemoglobin concentration in those treated with plasma compared to no treatment. The change in INR was small and corrected to less than 1.5 in minority of patients. Large trials are required to establish if plasma is safe and efficacious.

Protocol of a randomized controlled trial to test the effects of client-centered Representative Payee Services on antiretroviral therapy adherence among marginalized people living with HIV.

BACKGROUND: Client-Centered Representative Payee (CCRP) is an intervention modifying implementation of a current policy of the US Social Security Administration, which appoints organizations to serve as financial payees on behalf of vulnerable individuals receiving Social Security benefits. By ensuring beneficiaries' bills are paid while supporting their self-determination, this structural intervention may mitigate the effects of economic disadvantage to improve housing and financial stability, enabling self-efficacy for health outcomes and improved antiretroviral therapy adherence. This randomized controlled trial will test the impact of CCRP on marginalized people living with HIV (PLWH). We hypothesize that helping participants to pay their rent and other bills on time will improve housing stability and decrease financial stress. METHODS: PLWH (n = 160) receiving services at community-based organizations will be randomly assigned to the CCRP intervention or the standard of care for 12 months. Fifty additional participants will be enrolled into a non-randomized ("choice") study allowing participant selection of the CCRP intervention or control. The primary outcome is HIV medication adherence, assessed via the CASE adherence index, viral load, and CD4 counts. Self-assessment data for ART adherence, housing instability, self-efficacy for health behaviors, financial stress, and retention in care will be collected at baseline, 3, 6, and 12 months. Viral load, CD4, and appointment adherence data will be collected at baseline, 6, 12, 18, and 24 months from medical records. Outcomes will be compared by treatment group in the randomized trial, in the non-randomized cohort, and in the combined cohort. Qualitative data will be collected from study participants, eligible non-participants, and providers to explore underlying mechanisms of adherence, subjective responses to the intervention, and implementation barriers and facilitators. DISCUSSION: The aim of this study is to determine if CCRP improves health outcomes for vulnerable PLWH. Study outcomes may provide information about supports needed to help economically fragile PLWH improve health outcomes and ultimately improve HIV health disparities. In addition, findings may help to refine service delivery including the provision of representative payee to this often-marginalized population. This protocol was prospectively registered on May 22, 2018 with ClinicalTrials.gov (NCT03561103) .

Breastfeeding factors and risk of epithelial ovarian cancer.

OBJECTIVE: Previous studies suggest that breastfeeding reduces epithelial ovarian cancer (EOC) risk. However, the effects of age, timing and episode details on the EOC-breastfeeding relationship have not been examined. The objective of this study was to examine the association between breastfeeding factors and epithelial ovarian cancer. METHODS: We examined breastfeeding factors among parous women in a population-based, case-control study conducted in Pennsylvania, Ohio, and New York from 2003 to 2008. We compared 689 incident EOC cases to 1572 community controls. Multivariable unconditional logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) associated with breastfeeding patterns adjusting for potential confounders. RESULTS: Compared to never breastfeeding, breastfeeding any offspring was associated with a 30% reduction in EOC risk (OR = 0.70; 95%CI = 0.58-0.85). That association lasted more than 30 years (OR = 0.69, 95%CI = 0.53-0.88). An average breastfeeding episode of 3 months was also associated with reduced risk (OR = 0.73, 95%CI = 0.58-0.80). A greater number of breastfeeding episodes was associated with greater risk reduction (OR = 0.78, 95%CI = 0.64-0.96 and OR = 0.49, 95%CI = 0.36-0.68 1-2 and 3+ episodes, respectively, compared to never breastfed, trend p = 0.01). Longer breastfeeding duration was also associated with reduced risk (OR = 0.75 and 0.62 for less than and greater than 1-year total duration, respectively, compared to never breastfed). An earlier age at first breastfeeding was further associated with increased protection (OR = 0.50-0.80, for first episode at age <25, 25-29, and 30+, respectively, trend p = 0.001). CONCLUSIONS: Breastfeeding for as few as 3 months is associated with reduced EOC risk. Although this association decreases over time, it persists for more than 30 years. Longer cumulative duration, increasing number of breastfeeding episodes, and earlier age at first breastfeeding episode are each associated with increased benefit.

Troponin and Cardiac Events in Stable Ischemic Heart Disease and Diabetes.

BACKGROUND: Cardiac troponin concentrations are used to identify patients who would benefit from urgent revascularization for acute coronary syndromes. We hypothesized that they might be used in patients with stable ischemic heart disease to identify those at high risk for cardiovascular events who might also benefit from prompt coronary revascularization. METHODS: We measured the cardiac troponin T concentration at baseline with a high-sensitivity assay in 2285 patients who had both type 2 diabetes and stable ischemic heart disease and were enrolled in the Bypass Angioplasty Revascularization Investigation in Type 2 Diabetes trial. We tested for an association between the troponin T concentration and a composite end point of death from cardiovascular causes, myocardial infarction, or stroke; we then evaluated whether random assignment to prompt revascularization reduced the rate of the composite end point in patients with an abnormal troponin T concentration (≥14 ng per liter) as compared with those with a normal troponin T concentration (<14 ng per liter). RESULTS: Of the 2285 patients, 2277 (99.6%) had detectable (≥3 ng per liter) troponin T concentrations and 897 (39.3%) had abnormal troponin T concentrations at baseline. The 5-year rate of the composite end point was 27.1% among the patients who had had abnormal troponin T concentrations at baseline, as compared with 12.9% among those who had had normal baseline troponin T concentrations. In models that were adjusted for cardiovascular risk factors, severity of diabetes, electrocardiographic abnormalities, and coronary anatomy, the hazard ratio for the composite end point among patients with abnormal troponin T concentrations was 1.85 (95% confidence interval [CI], 1.48 to 2.32; P<0.001). Among patients with abnormal troponin T concentrations, random assignment to prompt revascularization, as compared with medical therapy alone, did not result in a significant reduction in the rate of the composite end point (hazard ratio, 0.96; 95% CI, 0.74 to 1.25). CONCLUSIONS: The cardiac troponin T concentration was an independent predictor of death from cardiovascular causes, myocardial infarction, or stroke in patients who had both type 2 diabetes and stable ischemic heart disease. An abnormal troponin T value of 14 ng per liter or higher did not identify a subgroup of patients who benefited from random assignment to prompt coronary revascularization. (Funded by the National Institutes of Health and Roche Diagnostics; BARI 2D ClinicalTrials.gov number, NCT00006305.).

Experience With a New Process - Condition T - for Uncontrolled Donation After Circulatory Determination of Death in a University Emergency Department.

BACKGROUND: In the United States, organ donation after circulatory death (DCD) determination is increasing among those who are removed from life-sustaining therapy but is rare when death is unexpected. We created a program for uncontrolled DCD (uDCD). METHODS: A comprehensive program was created to train personnel to identify and respond quickly to potential donors after unexpected death. The process termed Condition T was implemented in the emergency department (ED) of 2 academic medical centers. All ED deaths were screened for uDCD potential. Eligible donors included patients with preexisting donor designation who received cardiopulmonary resuscitation, failed to respond, and were pronounced dead. RESULTS: Over 350 nurses, physicians, perfusionists, organ procurement personnel, and administrators were trained. From February 2009 to June 2010, a total of 18 patients were potential Condition T candidates. Six Condition T responses were triggered. Three donors underwent cannulation, and 4 organs were recovered (3 kidney and 1 liver) from 2 donors. Time from Condition T trigger to perfusion with organ preservation solution ranged from 14 to 22.3 minutes. Perfusion duration was 197 and 221 minutes. No recovered organs were transplanted because biopsies showed prolonged warm ischemia. CONCLUSIONS: It is feasible to create a process to rapidly intervene in the ED for uDCD. However, no organ transplants resulted. The utility and sustainability of an uDCD program in this particular setting are questionable.

Rosiglitazone and outcomes for patients with diabetes mellitus and coronary artery disease in the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial.

BACKGROUND: Rosiglitazone improves glycemic control for patients with type 2 diabetes mellitus, but there remains controversy regarding an observed association with cardiovascular hazard. The cardiovascular effects of rosiglitazone for patients with coronary artery disease remain unknown. METHODS AND RESULTS: To examine any association between rosiglitazone use and cardiovascular events among patients with diabetes mellitus and coronary artery disease, we analyzed events among 2368 patients with type 2 diabetes mellitus and coronary artery disease in the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial. Total mortality, composite death, myocardial infarction, and stroke, and the individual incidence of death, myocardial infarction, stroke, congestive heart failure, and fractures, were compared during 4.5 years of follow-up among patients treated with rosiglitazone versus patients not receiving a thiazolidinedione by use of Cox proportional hazards and Kaplan-Meier analyses that included propensity matching. After multivariable adjustment, among patients treated with rosiglitazone, mortality was similar (hazard ratio [HR], 0.83; 95% confidence interval [CI], 0.58-1.18), whereas there was a lower incidence of composite death, myocardial infarction, and stroke (HR, 0.72; 95% CI, 0.55-0.93) and stroke (HR, 0.36; 95% CI, 0.16-0.86) and a higher incidence of fractures (HR, 1.62; 95% CI, 1.05-2.51); the incidence of myocardial infarction (HR, 0.77; 95% CI, 0.54-1.10) and congestive heart failure (HR, 1.22; 95% CI, 0.84-1.82) did not differ significantly. Among propensity-matched patients, rates of major ischemic cardiovascular events and congestive heart failure were not significantly different. CONCLUSIONS: Among patients with type 2 diabetes mellitus and coronary artery disease in the BARI 2D trial, neither on-treatment nor propensity-matched analysis supported an association of rosiglitazone treatment with an increase in major ischemic cardiovascular events. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00006305.

Changes in six categories of alcohol-attributable mortality from before to during the early phases of the COVID-19 pandemic.

OBJECTIVE: The shelter-in-place mandates enacted early in the COVID-19 pandemic resulted in changes in alcohol use and consequent outcomes. We assessed changes in six categories of season-specific alcohol-attributable mortality from before to during the early phases of the COVID-19 pandemic in the U.S. METHODS: We used logistic regression models to assess alcohol-attributable mortality in the U.S. from 2017 through 2020 (n=11,632,725 decedents ages 18 and older). Outcomes included chronic fully alcohol-attributable deaths, poisonings, motor vehicle accidents, suicides, homicides, and falls. Exposure variables included year, season, the interaction between the year 2020 and season, rurality, the interaction between the year 2020 and rurality, decedent age, sex, race, ethnicity, marital status, and education. RESULTS: Compared to 2019, season-specific mortality age-adjusted rates of chronic fully alcohol-attributable deaths, homicides, poisonings, and falls increased during the COVID-19 pandemic. Suicide rates decreased in most 2020 seasons relative to the same seasons in 2019. Motor vehicle deaths decreased in the spring of 2020 vs. 2019. Relative to dying by any other cause, the odds of death by chronic fully alcohol-attributable causes and poisonings were higher across seasons in 2020 vs. 2019. The odds of death by suicide were higher among residents of rural counties in the spring of 2020 vs. 2019. CONCLUSIONS: There were distinct temporal changes in six types of alcohol-attributable deaths during the early phases of the COVID-19 pandemic.

Clinical and angiographic risk stratification and differential impact on treatment outcomes in the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial.

BACKGROUND: The Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial assigned patients with type 2 diabetes mellitus to prompt coronary revascularization plus intensive medical therapy versus intensive medical therapy alone and reported no significant difference in mortality. Among patients selected for coronary artery bypass graft surgery, prompt coronary revascularization was associated with a significant reduction in death/myocardial infarction/stroke compared with intensive medical therapy. We hypothesized that clinical and angiographic risk stratification would affect the effectiveness of the treatments overall and within revascularization strata. METHODS AND RESULTS: An angiographic risk score was developed from variables assessed at randomization; independent prognostic factors were myocardial jeopardy index, total number of coronary lesions, prior coronary revascularization, and left ventricular ejection fraction. The Framingham Risk Score for patients with coronary disease was used to summarize clinical risk. Cardiovascular event rates were compared by assigned treatment within high-risk and low-risk subgroups. Overall, no outcome differences between the intensive medical therapy and prompt coronary revascularization groups were seen in any risk stratum. The 5-year risk of death/myocardial infarction/stroke was 36.8% for intensive medical therapy compared with 24.8% for prompt coronary revascularization among the 381 coronary artery bypass graft surgery-selected patients in the highest angiographic risk tertile (P=0.005); this treatment effect was amplified in patients with both high angiographic and high Framingham risk (47.3% intensive medical therapy versus 27.1% prompt coronary revascularization; P=0.010; hazard ratio=2.10; P=0.009). Treatment group differences were not significant in other clinical-angiographic risk groups within the coronary artery bypass graft surgery stratum, or in any subgroups within the percutaneous coronary intervention stratum. CONCLUSION: Among patients with diabetes mellitus and stable ischemic heart disease, a strategy of prompt coronary artery bypass graft surgery significantly reduces the rate of death/myocardial infarction MI/stroke in those with extensive coronary artery disease or impaired left ventricular function. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00006305.

Liberal versus restrictive transfusion thresholds for patients with symptomatic coronary artery disease.

BACKGROUND: Prior trials suggest it is safe to defer transfusion at hemoglobin levels above 7 to 8 g/dL in most patients. Patients with acute coronary syndrome may benefit from higher hemoglobin levels. METHODS: We performed a pilot trial in 110 patients with acute coronary syndrome or stable angina undergoing cardiac catheterization and a hemoglobin <10 g/dL. Patients in the liberal transfusion strategy received one or more units of blood to raise the hemoglobin level ≥10 g/dL. Patients in the restrictive transfusion strategy were permitted to receive blood for symptoms from anemia or for a hemoglobin <8 g/dL. The predefined primary outcome was the composite of death, myocardial infarction, or unscheduled revascularization 30 days post randomization. RESULTS: Baseline characteristics were similar between groups except age (liberal, 67.3; restrictive, 74.3). The mean number of units transfused was 1.6 in the liberal group and 0.6 in the restrictive group. The primary outcome occurred in 6 patients (10.9%) in the liberal group and 14 (25.5%) in the restrictive group (risk difference = 15.0%; 95% confidence interval of difference 0.7% to 29.3%; P = .054 and adjusted for age P = .076). Death at 30 days was less frequent in liberal group (n = 1, 1.8%) compared to restrictive group (n = 7, 13.0%; P = .032). CONCLUSIONS: The liberal transfusion strategy was associated with a trend for fewer major cardiac events and deaths than a more restrictive strategy. These results support the feasibility of and the need for a definitive trial.

Severity of diabetic foot infection and rate of limb salvage.

BACKGROUND: Foot infections are limb-threatening complications in patients with diabetes mellitus (DM), and proper classification of the severity of diabetic foot infection (DFI) is important in determining an effective antibiotic regimen, the need for hospitalization and surgery, and the risk of amputation. Our hypothesis was that patients with severe DFI would have a longer hospitalization than those with moderate DFI. The purposed of this study was 2-fold. The first purpose was to define DFI using readily available clinical information and objective parameters outlined by consensus statements. The second purpose of this study was to assess rates of amputation and limb salvage for hospitalized patients with DFI. METHODS: The database of a single academic foot and ankle program was reviewed for patients who were hospitalized for a DFI from 2006 to 2011. Inpatient and outpatient electronic medical records identified 100 patients. Severe DFI was defined as having 2 or more objective findings of systemic toxicity and/or metabolic instability at the time of initial assessment. RESULTS: The length of stay was significantly shorter for patients with a moderate infection than for those with a severe infection (median 5 days vs 8 days, P = .021). A nonsignificant trend was observed that indicated higher rates of limb salvage in patients with moderate infections compared with patients with severe infections (94% vs 80%, P = .081). CONCLUSION: Patients with severe DFI had a median hospital stay that was 60% longer than that of patients with moderate DFI. In this sample, 55% of patients with a severe DFI required some type of amputation compared with 42% of patients with a moderate DFI. LEVEL OF EVIDENCE: Level III, retrospective control cohort study.

Lifetime ovulatory years and risk of epithelial ovarian cancer: a multinational pooled analysis.

BACKGROUND: The role of ovulation in epithelial ovarian cancer (EOC) is supported by the consistent protective effects of parity and oral contraceptive use. Whether these factors protect through anovulation alone remains unclear. We explored the association between lifetime ovulatory years (LOY) and EOC. METHODS: LOY was calculated using 12 algorithms. Odds ratios (ORs) and 95% confidence intervals (CIs) estimated the association between LOY or LOY components and EOC among 26 204 control participants and 21 267 case patients from 25 studies. To assess whether LOY components act through ovulation suppression alone, we compared beta coefficients obtained from regression models with expected estimates assuming 1 year of ovulation suppression has the same effect regardless of source. RESULTS: LOY was associated with increased EOC risk (OR per year increase = 1.014, 95% CI = 1.009 to 1.020 to OR per year increase = 1.044, 95% CI = 1.041 to 1.048). Individual LOY components, except age at menarche, also associated with EOC. The estimated model coefficient for oral contraceptive use and pregnancies were 4.45 times and 12- to 15-fold greater than expected, respectively. LOY was associated with high-grade serous, low-grade serous, endometrioid, and clear cell histotypes (ORs per year increase = 1.054, 1.040, 1.065, and 1.098, respectively) but not mucinous tumors. Estimated coefficients of LOY components were close to expected estimates for high-grade serous but larger than expected for low-grade serous, endometrioid, and clear cell histotypes. CONCLUSIONS: LOY is positively associated with nonmucinous EOC. Differences between estimated and expected model coefficients for LOY components suggest factors beyond ovulation underlie the associations between LOY components and EOC in general and for non-HGSOC.

Peroxisome proliferator-activated receptor pathway gene polymorphism associated with extent of coronary artery disease in patients with type 2 diabetes in the bypass angioplasty revascularization investigation 2 diabetes trial.

BACKGROUND: Coronary artery disease (CAD) is the major cause of death in patients with type 2 diabetes mellitus. Although demographic and clinical factors associated with extent of CAD in patients with diabetes mellitus have been described, genetic factors have not. We hypothesized that genetic variation in peroxisome proliferator-activated receptor (PPAR) pathway genes, important in diabetes mellitus and atherosclerosis, would be associated with extent of CAD in patients with diabetes mellitus. METHODS AND RESULTS: We genotyped 1043 patients (702 white, 175 blacks) from the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) genetic cohort for 3351 variants in 223 PPAR pathway genes using a custom targeted-genotyping array. Angiographic end points were determined by a core laboratory. In whites, a single variant (rs1503298) in TLL1 was significantly (P=5.5 × 10(-6)) associated with extent of CAD, defined as number of lesions with percent diameter stenosis ≥20%, after stringent Bonferroni correction for all 3351 single nucleotide polymorphisms. This association was validated in the diabetic subgroups of 2 independent cohorts, the Translational Research Investigating Underlying Disparities in Acute Myocardial Infarction Patients' Health Status (TRIUMPH) post-myocardial infarction registry and the prospective Family Heart Study (FHS) of individuals at risk for CAD. TLL1rs1503298 was also significantly associated with extent of severe CAD (≥70% diameter stenosis; P=3.7 × 10(-2)) and myocardial jeopardy index (P=8.7 × 10(-4)). In general linear regression modeling, TLL1rs1503298 explained more variance of extent of CAD than the previously determined clinical factors. CONCLUSIONS: We identified a variant in a single PPAR pathway gene, TLL1, that is associated with the extent of CAD independently of clinical predictors, specifically in patients with type 2 diabetes mellitus and CAD. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00006305.