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Depression and depressive symptoms predict poor adherence to medical therapy, but the association is complex, nonspecific, and difficult to interpret. Understanding this association may help to identify the mechanism explaining the results of interventions that improve both medical therapy adherence and depressive symptoms as well as determine the importance of targeting depression in adherence interventions. We previously demonstrated that Managed Problem Solving (MAPS) focused on HIV medication adherence improved adherence and viral load in patients initiating a new antiretroviral regimen. Here, we assessed whether MAPS improved depressive symptoms and in turn, whether changes in depressive symptoms mediated changes in adherence and treatment outcomes. We compared MAPS to usual care with respect to presence of depressive symptoms during the trial using logistic regression. We then assessed whether MAPS' effect on depressive symptoms mediated the relationship between MAPS and adherence and virologic outcomes using linear and logistic regression, respectively. Mediation was defined by the disappearance of the mathematical association between MAPS and the outcomes when the proposed mediator was included in regression models. Although MAPS participants had a lower rate of depressive symptoms (OR = 0.45, 95% confidence interval 0.21-0.93), there was no evidence of mediation of the effects of MAPS on adherence and virological outcome by improvements in depression. Thus, interventions for medication adherence may not need to address depressive symptoms in order to impact both adherence and depression; this remains to be confirmed, however, in other data.

Background: Strains on the capacities of intensive care units (ICUs) may influence the quality of ICU-to-floor transitions., Objective: To determine how 3 metrics of ICU capacity strain (ICU census, new admissions, and average acuity) measured on days of patient discharges influence ICU length of stay (LOS) and post-ICU discharge outcomes., Design: Retrospective cohort study from 2001 to 2008., Setting: 155 ICUs in the United States., Patients: 200 730 adults discharged from ICUs to hospital floors., Measurements: Associations between ICU capacity strain metrics and discharged patient ICU LOS, 72-hour ICU readmissions, subsequent in-hospital death, post-ICU discharge LOS, and hospital discharge destination., Results: Increases in the 3 strain variables on the days of ICU discharge were associated with shorter preceding ICU LOS (all P < 0.001) and increased odds of ICU readmissions (all P < 0.050). Going from the 5th to 95th percentiles of strain was associated with a 6.3-hour reduction in ICU LOS (95% CI, 5.3 to 7.3 hours) and a 1.0% increase in the odds of ICU readmission (CI, 0.6% to 1.5%). No strain variable was associated with increased odds of subsequent death, reduced odds of being discharged home from the hospital, or longer total hospital LOS., Limitation: Long-term outcomes could not be measured., Conclusion: When ICUs are strained, triage decisions seem to be affected such that patients are discharged from the ICU more quickly and, perhaps consequentially, have slightly greater odds of being readmitted to the ICU. However, short-term patient outcomes are unaffected. These results suggest that bed availability pressures may encourage physicians to discharge patients from the ICU more efficiently and that ICU readmissions are unlikely to be causally related to patient outcomes., Primary Funding Source: Agency for Healthcare Research and Quality; National Heart, Lung, and Blood Institute; and Society of Critical Care Medicine.

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., (Copyright © 2013 John Wiley & Sons, Ltd.)

Purpose: Endometrial cancers have long been divided into estrogen-dependent type I and the less common clinically aggressive estrogen-independent type II. Little is known about risk factors for type II tumors because most studies lack sufficient cases to study these much less common tumors separately. We examined whether so-called classical endometrial cancer risk factors also influence the risk of type II tumors., Patients and Methods: Individual-level data from 10 cohort and 14 case-control studies from the Epidemiology of Endometrial Cancer Consortium were pooled. A total of 14,069 endometrial cancer cases and 35,312 controls were included. We classified endometrioid (n = 7,246), adenocarcinoma not otherwise specified (n = 4,830), and adenocarcinoma with squamous differentiation (n = 777) as type I tumors and serous (n = 508) and mixed cell (n = 346) as type II tumors., Results: Parity, oral contraceptive use, cigarette smoking, age at menarche, and diabetes were associated with type I and type II tumors to similar extents. Body mass index, however, had a greater effect on type I tumors than on type II tumors: odds ratio (OR) per 2 kg/m(2) increase was 1.20 (95% CI, 1.19 to 1.21) for type I and 1.12 (95% CI, 1.09 to 1.14) for type II tumors (P heterogeneity < .0001). Risk factor patterns for high-grade endometrioid tumors and type II tumors were similar., Conclusion: The results of this pooled analysis suggest that the two endometrial cancer types share many common etiologic factors. The etiology of type II tumors may, therefore, not be completely estrogen independent, as previously believed.

Background: Black women are more likely than white women to have an aggressive subtype of breast cancer that is associated with higher mortality and this may contribute to the observed black-white difference in mortality. However, few studies have investigated the black-white disparity in mortality risk stratified by breast cancer subtype, defined by estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) status. Furthermore, it is not known whether additional consideration of p53 protein status influences black-white differences in mortality risk observed when considering subtypes defined by ER, PR and HER2 status., Methods: Four biomarkers were assessed by immunohistochemistry in paraffin-embedded breast tumor tissue from 1,204 (523 black, 681 white) women with invasive breast cancer, aged 35-64 years at diagnosis, who accrued a median of 10 years' follow-up. Multivariable Cox proportional hazards regression models were fit to assess subtype-specific black-white differences in mortality risk., Results: No black-white differences in mortality risk were observed for women with triple negative (ER-negative [ER-], PR-, and HER2-) subtype. However, older (50-64 years) black women had greater overall mortality risk than older white women if they had been diagnosed with luminal A (ER-positive [ER+] or PR+ plus HER2-) breast cancer (all-cause hazard ratio, HR, 1.88; 95% confidence interval, CI, 1.18 to 2.99; breast cancer-specific HR, 1.51; 95% CI, 0.83 to 2.74). This black-white difference among older women was further confined to those with luminal A/p53- tumors (all-cause HR, 2.22; 95% CI, 1.30 to 3.79; breast cancer-specific HR, 1.89; 95% CI, 0.93 to 3.86). Tests for homogeneity of race-specific HRs comparing luminal A to triple negative subtype and luminal A/p53- to luminal A/p53+ subtype did not achieve statistical significance, although statistical power was limited., Conclusions: Our findings suggest that the subtype-specific black-white difference in mortality risk occurs mainly among older women diagnosed with luminal A/p53- breast cancer, which is most likely treatable. These results further suggest that factors other than subtype may be relatively more important in explaining the increased mortality risk seen in older black women.

Jeffrey pine, Pinus jeffreyi Greville and Balfour, is a dominant yellow pine and important overstory component of forests growing on diverse sites from southwestern Oregon to Baja California to western Nevada. The Jeffrey pine beetle, Dendroctonus jeffreyi Hopkins (Coleoptera: Curculionidae: Scolytinae), is monophagous on Jeffrey pine and its primary insect pest. Despite the importance of P. jeffreyi, difficult terrain, environmental concerns, and lack of roads can constrain pest management activities. Semiochemicals are often easier to apply and more environmentally acceptable than other options, but they are lacking in this system. Attractants have been identified, but field bioassays have been limited because of infrequent or short duration outbreaks and a lack of beetles during nonoutbreak periods. Disruptant semiochemicals have not been assessed for D. jeffreyi during outbreak conditions; however, commercially available semiochemicals have been implicated as disruptants for this bark beetle. The objective of this study was to identify the most effective commercially available attractant and disruptant semiochemicals for D. jeffreyi. Our highest observed catch occurred with the blend of 5% 1-heptanol and 95% n-heptane. When this was used to challenge potential disruptant semiochemicals, the combination of S-(-)-verbenone and the green leaf volatile blend (cis-3-Hexenol and 1-Hexanol) reduced trap catch by ≍80%. However, frontalin was most effective, reducing the number of D. jeffreyi caught by >96%. Within each year of the study, the percentage female of D. jeffreyi caught with our attractant decreased from start to end of the experimental period. On average, our first collection in a year (mid-June to early July) was 59% female, whereas our last (mid-August) was 34%. Frontalin was equally or more effective against females (the pioneering sex) than males, providing optimism that semiochemical disruption may be possible for protecting Jeffrey pines from D. jeffreyi.

Large, "practical" or streamlined trials (LSTs) are used to study the effectiveness and/or safety of medicines in real world settings with minimal study imposed interventions. While LSTs have benefits over traditional randomized clinical trials and observational studies, there are inherent challenges to their conduct. Enrollment and follow-up of a large study sample of patients with mental illness pose a particular difficulty. To assist in overcoming operational barriers in future LSTs in psychiatry, this paper describes the recruitment and observational follow-up strategies used for the ZODIAC study, an international, open-label LST, which followed 18,239 persons randomly assigned to one of two treatments indicated for schizophrenia for 1 year. ZODIAC enrolled patients in 18 countries in North America, South America, Europe, and Asia using broad study entry criteria and required minimal clinical care intervention. Recruitment of adequate numbers and continued engagement of both study centers and subjects were significant challenges. Strategies implemented to mitigate these in ZODIAC include global study expansion, study branding, field coordinator and site relations programs, monthly site newsletters, collection of alternate contact information, conduct of national death index (NDI) searches, and frequent sponsor, contract research organization (CRO) and site interaction to share best practices and address recruitment challenges quickly. We conclude that conduct of large LSTs in psychiatric patient populations is feasible, but importantly, realistic site recruitment goals and maintaining site engagement are key factors that need to be considered in early study planning and conduct., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background: Adherence to antiretroviral therapy is critical to successful treatment of human immunodeficiency virus (HIV). Few interventions have been demonstrated to improve both adherence and virologic outcomes. We sought to determine whether an intervention derived from problem solving theory, Managed Problem Solving (MAPS), would improve antiretroviral outcomes., Methods: We conducted a randomized investigator blind trial of MAPS compared with usual care in HIV-1 infected individuals at 3 HIV clinics in Philadelphia, Pennsylvania. Eligible patients had plasma HIV-1 viral loads greater than 1000 copies/mL and were initiating or changing therapy. Managed Problem Solving consists of 4 in-person and 12 telephone-based meetings with a trained interventionist, then monthly follow-up calls for a year. Primary outcome was medication adherence measured using electronic monitors, summarized as fraction of doses taken quarterly over 1 year. Secondary outcome was undetectable HIV viral load over 1 year. We assessed 218 for eligibility, with 190 eligible and 180 enrolled, 91 randomized to MAPS and 89 to usual care. Fifty-six participants were lost to follow-up: 33 in the MAPS group and 23 in usual care group., Results: In primary intention-to-treat analyses, the odds of being in a higher adherence category was 1.78 (95% CI,1.07-2.96) times greater for MAPS than usual care. In secondary analyses, the odds of an undetectable viral load was 1.48 (95% CI, 0.94-2.31) times greater for MAPS than usual care. In as-treated analyses, the effect of MAPS was stronger for both outcomes. There was neither a difference by prior treatment status nor change in effect over time., Conclusions: Managed Problem Solving is an effective antiretroviral adherence intervention over the first year with a new regimen. It was equally effective at improving adherence in treatment experienced and naïve patients and did not lose effect over time. Implementation of MAPS should be strongly considered where resources are available., Trial Registration: clinicaltrials.gov Identifier: NCT00130273., Competing Interests: The authors have declared that no competing interests exist.

Main Objective: To compare the incidence rates of serious cardiovascular events in adult initiators of amphetamines or atomoxetine to rates in non-users., Methods: This was a retrospective cohort study of new amphetamines (n=38,586) or atomoxetine (n=20,995) users. Each medication user was matched to up to four non-users on age, gender, data source, and state (n=238,183). The following events were primary outcomes of interest 1) sudden death or ventricular arrhythmia, 2) stroke, 3) myocardial infarction, 4) a composite endpoint of stroke or myocardial infarction. Cox proportional hazard regression was used to calculate propensity-adjusted hazard ratios for amphetamines versus matched non-users and atomoxetine versus matched non-users, with intracluster dependence within matched sets accounted for using a robust sandwich estimator., Results: The propensity-score adjusted hazard ratio for amphetamines use versus non-use was 1.18 (95% CI: 0.55-2.54) for sudden death/ventricular arrhythmia, 0.80 (95% CI: 0.44-1.47) for stroke, 0.75 (95% CI: 0.42-1.35) for myocardial infarction, and 0.78 (95% CI: 0.51-1.19) for stroke/myocardial infarction. The propensity-score adjusted hazard ratio for atomoxetine use versus non-use was 0.41 (95% CI: 0.10-1.75) for sudden death/ventricular arrhythmia, 1.30 (95% CI: 0.52-3.29) for stroke, 0.56 (95% CI: 0.16-2.00) for myocardial infarction, and 0.92 (95% CI: 0.44-1.92) for stroke/myocardial infarction., Conclusions: Initiation of amphetamines or atomoxetine was not associated with an elevated risk of serious cardiovascular events. However, some of the confidence intervals do not exclude modest elevated risks, e.g. for sudden death/ventricular arrhythmia.

Introduction: The association of breast cancer patients’ mortality with estrogen receptor (ER) status (ER + versus ER-) has been well studied. However, little attention has been paid to the relationship between the quantitative measures of ER expression and mortality., Methods: We evaluated the association between semi-quantitative, immunohistochemical staining of ER in formalin-fixed paraffin-embedded breast carcinomas and breast cancer-specific mortality risk in an observational cohort of invasive breast cancer in 681 white women and 523 black women ages 35-64 years at first diagnosis of invasive breast cancer, who were followed for a median of 10 years. The quantitative measures of ER examined here included the percentage of tumor cell nuclei positively stained for ER, ER Histo (H)-score, and a score based on an adaptation of an equation presented by Cuzick and colleagues, which combines weighted values of ER H-score, percentage of tumor cell nuclei positively stained for the progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) results. This is referred to as the ER/PR/HER2 score., Results: After controlling for age at diagnosis, race, study site, tumor stage, and histologic grade in multivariable Cox proportional hazards regression models, both percentage of tumor cell nuclei positively stained for ER (Ptrend = 0.0003) and the ER H-score (Ptrend = 0.0004) were inversely associated with breast cancer-specific mortality risk. The ER/PR/HER2 score was positively associated with breast cancer-specific mortality risk in women with ER + tumor (Ptrend = 0.001). Analyses by race revealed that ER positivity was associated with reduced risk of breast cancer-specific mortality in white women and black women. The two quantitative measures for ER alone provided additional discrimination in breast cancer-specific mortality risk only among white women with ER + tumors (both Ptrend ≤ 0.01) while the ER/PR/HER2 score provided additional discrimination for both white women (Ptrend = 0.01) and black women (Ptrend = 0.03) with ER + tumors., Conclusions: Our data support quantitative immunohistochemical measures of ER, especially the ER/PR/HER2 score, as a more precise predictor for breast cancer-specific mortality risk than a simple determination of ER positivity.

Context: Antipsychotic drugs have been linked to QT-interval prolongation, a presumed marker of cardiac risk, and torsade de pointes., Objective: To examine the associations between antipsychotics and 1) outpatient-originated sudden cardiac death and ventricular arrhythmia (SD/VA) and 2) all-cause death., Design: Two retrospective cohort studies., Setting: Medicaid programs of California, Florida, New York, Ohio and Pennsylvania., Patients: Incident antipsychotic users aged 30-75 years., Main Outcome Measures: 1) Incident, first-listed emergency department or principal inpatient SD/VA diagnoses; and 2) death reported in the Social Security Administration Death Master File., Results: Among 459,614 incident antipsychotic users, the incidences of SD/VA and death were 3.4 and 35.1 per 1,000 person-years, respectively. Compared to olanzapine as the referent, adjusted hazard ratios (HRs) for SD/VA were 2.06 (95% CI, 1.20-3.53) for chlorpromazine, 1.72 (1.28-2.31) for haloperidol, and 0.73 (0.57-0.93) for quetiapine. Adjusted HRs for perphenazine and risperidone were consistent with unity. In a subanalysis limited to first prescription exposures, HRs for chlorpromazine and haloperidol were further elevated (2.54 [1.07-5.99] and 2.68 [1.59-4.53], respectively), with the latter exhibiting a dose-response relationship. Results for death were similar., Conclusions: Haloperidol and chlorpromazine had less favorable cardiac safety profiles than olanzapine. Among atypical agents, risperidone had a similar cardiac safety profile to olanzapine, whereas quetiapine was associated with 30% and 20% lower risks of SD/VA and death, respectively, compared to olanzapine. These measured risks do not correlate well with average QT prolongation, further supporting the notion that average QT prolongation may be a poor surrogate of antipsychotic arrhythmogenicity.

Purpose: To describe the design and rationale of a series of postmarketing studies to examine the safety of saxagliptin, an oral dipeptidyl peptidase-4 inhibitor for the treatment of type 2 diabetes mellitus, in real-world settings., Methods: We are conducting a series of retrospective cohort studies using two UK (General Practice Research Database, and The Health Improvement Network) and two US (Medicare, HealthCore Integrated Research Database(SM) ) data sources. The primary outcomes of interest will include (i) hospitalization with acute liver failure, (ii) hospitalization for acute kidney injury, (iii) hospitalization for severe hypersensitivity reactions, (iv) hospitalization for severe infections, (v) hospitalization with infections associated with T-lymphocyte dysfunction (i.e., herpes zoster, tuberculosis, or nontuberculous mycobacteria), and (vi) major cardiovascular events. Diagnosis codes for the outcomes of interest will be validated by medical record review within each data source. Projected use and estimated incidence rates of outcomes of interest suggest there will be at least 80% statistical power to detect a minimum hazard ratio of 1.5 for major cardiovascular events, 2.0 for acute kidney injury and severe infections, 2.4 for acute liver failure, and 4.0 for severe hypersensitivity reactions., Results: Forthcoming., Conclusions: This postmarketing safety assessment will provide important information regarding the safety of saxagliptin and could potentially identify important dipeptidyl peptidase-4 inhibitor class effects. The methods described may be useful to others planning similar evaluations., (Copyright © 2012 John Wiley & Sons, Ltd.)

Purpose: This study aims to examine the associations between proton pump inhibitors (PPIs), traditional nonsteroidal anti-inflammatory drugs (tNSAIDs), PPI + tNSAID co-exposure, and the development of the following: (i) acute interstitial nephritis (AIN), a specific kidney injury often attributed to these drugs, and (ii) acute kidney injury (AKI), a general kidney injury encompassing AIN., Methods: Two retrospective case-control studies were conducted, one for each outcome, within the General Practice Research Database. Cases were diagnostic-coded AIN (primary outcome) or AKI (secondary outcome) events. Controls were matched on age, sex, and general practitioner practice. Exposures were defined by the presence/absence of the following mutually exclusive therapies on the index date: (i) PPI alone; (ii) tNSAID alone; (iii) PPI + tNSAID; or (iv) neither PPI nor tNSAID (referent)., Results: Sixty-eight AIN cases and 3347 controls were identified. The adjusted odds ratios (ORs) for PPI and tNSAID exposures alone were 3.20 (0.80-12.79) and 1.90 (0.65-5.51), respectively. Numerous sensitivity analyses produced adjusted ORs for AIN between 3.0 and 7.7, and 1.6 and 1.9, respectively. We identified 27,982 AKI cases and 1,323,850 controls. The adjusted ORs for PPI alone, tNSAID alone, and PPI + tNSAID exposures were 1.05 (0.97-1.14), 1.31 (1.25-1.37), and 1.33 (1.07-1.64), respectively. Numerous sensitivity analyses produced adjusted ORs for AKI between 1.0 and 1.1, 1.1 and 1.3, and 1.3 and 1.4, respectively., Conclusions: Proton pump inhibitor exposure may increase the odds of AIN, but this result was not definitive and should be confirmed in a dataset with more AIN cases to allow for increased statistical precision. tNSAIDs, yet not PPIs, were associated with a significantly increased odds of AKI., (Copyright © 2012 John Wiley & Sons, Ltd.)

Childbearing at an older age has been associated with a lower risk of endometrial cancer, but whether the association is independent of the number of births or other factors remains unclear. Individual-level data from 4 cohort and 13 case-control studies in the Epidemiology of Endometrial Cancer Consortium were pooled. A total of 8,671 cases of endometrial cancer and 16,562 controls were included in the analysis. After adjustment for known risk factors, endometrial cancer risk declined with increasing age at last birth (P(trend) < 0.0001). The pooled odds ratio per 5-year increase in age at last birth was 0.87 (95% confidence interval: 0.85, 0.90). Women who last gave birth at 40 years of age or older had a 44% decreased risk compared with women who had their last birth under the age of 25 years (95% confidence interval: 47, 66). The protective association was similar across the different age-at-diagnosis groups and for the 2 major tumor histologic subtypes (type I and type II). No effect modification was observed by body mass index, parity, or exogenous hormone use. In this large pooled analysis, late age at last birth was independently associated with a reduced risk of endometrial cancer, and the reduced risk persisted for many years.

Background: Nearly all available treatments for pulmonary arterial hypertension have been approved based on change in 6-minute walk distance (Δ6MWD) as a clinically important end point, but its validity as a surrogate end point has never been shown. We aimed to validate the difference in Δ6MWD against the probability of a clinical event in pulmonary arterial hypertension trials., Methods and Results: First, to determine whether Δ6MWD between baseline and 12 weeks mediated the relationship between treatment assignment and development of clinical events, we conducted a pooled analysis of patient-level data from the 10 randomized placebo-controlled trials previously submitted to the US Food and Drug Administration (n=2404 patients). Second, to identify a threshold effect for the Δ6MWD that indicated a statistically significant reduction in clinical events, we conducted a meta-regression among 21 drug/dose-level combinations. Δ6MWD accounted for 22.1% (95% confidence interval, 12.1%- 31.1%) of the treatment effect (P<0.001). The meta-analysis showed an average difference in Δ6MWD of 22.4 m (95% confidence interval, 17.4-27.5 m), favoring active treatment over placebo. Active treatment decreased the probability of a clinical event (summary odds ratio, 0.44; 95% confidence interval, 0.33-0.57). The meta-regression revealed a significant threshold effect of 41.8 m., Conclusions: Our results suggest that Δ6MWD does not explain a large proportion of the treatment effect, has only modest validity as a surrogate end point for clinical events, and may not be a sufficient surrogate end point. Further research is necessary to determine whether the threshold value of 41.8 m is valid for long-term outcomes or whether it differs among trials using background therapy or lacking placebo controls entirely.

Objective: To compare the relative hazard of muscle toxicity, renal dysfunction, and hepatic dysfunction associated with the drug interaction between statins and concomitant medications that inhibit the CYP3A4 isoenzyme., Background: Although statins provide important clinical benefits related to mitigating the risk of cardiovascular events, this class of medications also has the potential for severe adverse reactions. The risk for adverse events may be potentiated by concomitant use of medications that interfere with statin metabolism., Methods: Data from The Health Improvement Network (THIN) from 1990 to 2008 were used to conduct a retrospective cohort study. Cohorts were created to evaluate each outcome (muscle toxicity, renal dysfunction, and hepatic dysfunction) independently. Each cohort included new statin initiators and compared the relative hazard of the outcome. The interaction ratio (I*R) was the primary contrast of interest. The I*R represents the relative effect of each statin type (statin 3A4 substrate vs. statin non-3A4 substrate) with a CYP3A4 inhibitor, independent of the effect of the statin type without a CYP3A4 inhibitor. We adjusted for confounding variables using the multinomial propensity score., Results: The median follow-up time per cohort was 1.5 years. There were 7889 muscle toxicity events among 362,809 patients and 792,665 person-years. The adjusted muscle toxicity I*R was 1.22 (95% confidence interval [CI] = 0.90-1.66). There were 1449 renal dysfunction events among 272,099 patients and 574,584 person-years. The adjusted renal dysfunction I*R was 0.91 (95%CI = 0.58-1.44). There were 1434 hepatic dysfunction events among 367,612 patients and 815,945 person-years. The adjusted hepatic dysfunction I*R was 0.78 (95%CI = 0.45-1.31)., Conclusions: Overall, this study found no difference in the relative hazard of muscle toxicity, renal dysfunction, or hepatic dysfunction for patients prescribed a statin 3A4 substrate versus a statin non-3A4 substrate with CYP3A4 inhibitor concomitancy., (Copyright © 2012 John Wiley & Sons, Ltd.)

Racial differences in breast cancer risk, including the risks of hormone receptor subtypes of breast cancer, have been previously reported. We evaluated whether variation in genes related to estrogen metabolism (COMT, CYP1A1, CYP1B1, CYP17A1, CYP19A1, ESR1, GSTM1, GSTP1, GSTT1, HSD17B1, SULT1A1, and UGT1A1) contributes to breast cancer risk and/or racial differences in risk within the CARE study, a multi-centered, population-based case-control study of breast cancer. Genetic variation was assessed as single nucleotide polymorphisms (SNPs), haplotypes, and SNP-hormone therapy (HT) interactions within a subset of 1,644 cases and 1,451 controls, including 949 Black women (493 cases and 456 controls), sampled from the CARE study population. No appreciable associations with breast cancer risk were detected for single SNPs or haplotypes in women overall. We detected SNP-HT interactions in women overall within CYP1B1 (rs1800440; p (het) = 0.003) and within CYP17A1 (rs743572; p (het) = 0.009) in which never users of HT were at a decreased risk of breast cancer, while ever users were at a non-significant increased risk. When investigated among racial groups, we detected evidence of an SNP-HT interaction with CYP1B1 in White women (p value = 0.02) and with CYP17A1 in Black women (p value = 0.04). This analysis suggests that HT use may modify the effect of variation in estrogen-related genes on breast cancer risk, which may affect Black and White women to a different extent.

Objectives: This study aims to assess whether digoxin has a different effect on mortality risk for women than it does for men in patients with heart failure (HF)., Design: This study uses the UK-based The Health Information Network population database in a cohort study of the impact of digoxin exposure on mortality for men and women who carry the diagnosis of HF. Digoxin exposure was assessed based on prescribing data. Multivariable Cox proportional hazards models were used to assess whether there was an interaction between sex and digoxin affecting mortality hazard., Setting: The setting was primary care outpatient practices., Participants: The study cohort consisted of 17 707 men and 19 227 women with the diagnosis of HF who contributed only time without digoxin exposure and 9487 men and 10 808 women with the diagnosis of HF who contributed time with digoxin exposure., Main Outcome Measures: The main outcome measure was all-cause mortality., Results: The primary outcome of this study was the absence of a large interaction between digoxin use and sex affecting mortality. For men, digoxin use was associated with a HR for mortality of 1.00, while for women, the HR was also 1.00 (p value for interaction 0.65). The results of sensitivity analyses were consistent with those of the primary analysis., Conclusion: Observational data do not support the concern that there is a substantial increased risk of mortality due to the use of digoxin in women. This finding is consistent with previous observational studies but discordant with results from a post hoc analysis of a randomised controlled trial of digoxin versus placebo.

Background: While evidence on the association between oral contraceptive (OC) use and breast cancer generally suggests little or no increased risk, the question of whether breast cancer risk varies by OC formulation remains controversial. Few studies have examined this issue because large samples and extensive OC histories are required., Study Design: We used data from a multicenter, population-based, case-control investigation. Women aged 35-64 years were interviewed. To explore the association between OC formulation and breast cancer risk, we used conditional logistic regression to derive adjusted odds ratios, and we used likelihood ratio tests for heterogeneity to assess whether breast cancer risk varied by OC formulation. Key OC exposure variables were ever use, current or former use, duration of use and time since last use. To strengthen inferences about specific formulations, we restricted most analyses to the 2282 women with breast cancer and the 2424 women without breast cancer who reported no OC use or exclusive use of one OC., Results: Thirty-eight formulations were reported by the 2674 women who used one OC; most OC formulations were used by only a few women. We conducted multivariable analyses on the 10 formulations that were each used by at least 50 women and conducted supplemental analyses on selected formulations of interest based on recent research. Breast cancer risk did not vary significantly by OC formulation, and no formulation was associated with a significantly increased breast cancer risk., Conclusions: These results add to the small body of literature on the relationship between OC formulation and breast cancer. Our data are reassuring in that, among women 35-64 years of age, we found no evidence that specific OC formulations increase breast cancer risk., (Published by Elsevier Inc.)

Objective: The authors sought to determine whether use of methylphenidate in adults is associated with elevated rates of serious cardiovascular events compared with rates in nonusers., Method: This was a cohort study of new users of methylphenidate based on administrative data from a five-state Medicaid database and a 14-state commercial insurance database. All new methylphenidate users with at least 180 days of prior enrollment were identified. Users were matched on data source, state, sex, and age to as many as four comparison subjects who did not use methylphenidate, amphetamines, or atomoxetine. A total of 43,999 new methylphenidate users were identified and matched to 175,955 nonusers. Events of primary interest were 1) sudden death or ventricular arrhythmia, 2) stroke, 3) myocardial infarction, and 4) a composite endpoint of stroke or myocardial infarction., Results: The age-standardized incidence rate per 1,000 person-years of sudden death or ventricular arrhythmia was 2.17 (95% CI=1.63-2.83) in methylphenidate users and 0.98 (95% CI=0.89-1.08) in nonusers, for an adjusted hazard ratio of 1.84 (95% CI=1.33-2.55). Dosage was inversely associated with risk. Adjusted hazard ratios for stroke, myocardial infarction, and the composite endpoint of stroke or myocardial infarction did not differ statistically from 1., Conclusions: Although initiation of methylphenidate was associated with a 1.8-fold increase in risk of sudden death or ventricular arrhythmia, the lack of a dose-response relationship suggests that this association may not be a causal one.

Background: Recently studied therapies for pulmonary arterial hypertension (PAH) have improved outcomes among populations of patients, but little is known about which patients are most likely to respond to specific treatments. Differences in endothelin-1 biology between sexes and between whites and blacks may lead to differences in patients' responses to treatment with endothelin receptor antagonists (ERAs)., Methods: We conducted pooled analyses of deidentified, patient-level data from six randomized placebo-controlled trials of ERAs submitted to the US Food and Drug Administration to elucidate heterogeneity in treatment response. We estimated the interaction between treatment assignment (ERA vs placebo) and sex and between treatment and white or black race in terms of the change in 6-min walk distance from baseline to 12 weeks., Results: Trials included 1,130 participants with a mean age of 49 years; 21% were men, 74% were white, and 6% were black. The placebo-adjusted response to ERAs was 29.7 m (95% CI, 3.7-55.7 m) greater in women than in men (P = .03). The placebo-adjusted response was 42.2 m for whites and -1.4 m for blacks, a difference of 43.6 m (95% CI, -3.5-90.7 m) (P = .07). Similar results were found in sensitivity analyses and in secondary analyses using the outcome of absolute distance walked., Conclusions: Women with PAH obtain greater responses to ERAs than do men, and whites may experience a greater treatment benefit than do blacks. This heterogeneity in treatment-response may reflect pathophysiologic differences between sexes and races or distinct disease phenotypes.

An innovative training program to provide clinical research training for clinicians was created in 1979 at the University of Pennsylvania School of Medicine, now the Perelman School of Medicine. The program's principal and continuing aim is to provide trainees mentored experiences and the training needed to become skilled independent investigators able to conduct clinical research and develop academic careers as independent clinical investigators.The authors identify the vision that led to the creation of the master of science in clinical epidemiology (MSCE) degree program and describe today's training program, including administration, oversight, participating faculty, and trainees. They also describe the program's core curriculum, elective options, seminars on ongoing research, training in the responsible conduct of research, professional development activities, and the development and completion of a closely mentored clinical research project.Approximately 35 new trainees enter the two- to three-year program annually. Funding is provided primarily by National Institutes of Health-funded training programs and supplemented by private industry, private foundations, and employee-based benefits. More than 500 individuals have received or are currently receiving training through the MSCE program. A large percentage of former trainees maintain full-time positions in academic medicine today.The authors identify some challenges that have been met and insights regarding funding, faculty, trainees, and curriculum. Ongoing challenges include recruiting trainees from some selected highly paid, procedure-oriented specialties, maintaining sufficient mentors for the continually increasing numbers of trainees, and distinguishing applicants who truly desire a primary research career from others.

A new model for the conduct of clinical research was established at the University of Pennsylvania (Penn) School of Medicine, now the Perelman School of Medicine, through the development of the interdepartmental Center for Clinical Epidemiology and Biostatistics in 1993 and the basic science Department of Biostatistics and Epidemiology in 1994. The authors describe the development and evolution of these novel structures.Five key objectives were achieved with these structures' creation: (1) Clinical faculty have the opportunity to be identified as both clinicians and epidemiologists, (2) nonclinical faculty have an academic "home," (3) clinical trainees are now educated in population medicine, which promotes its incorporation into their clinical practice, (4) population medicine and clinical medicine have become fully integrated, and (5) better epidemiologic research is conducted, informed by clinical insights.Today's center is the primary home for epidemiology and biostatistics at Penn, linking epidemiology, biostatistics, clinical medicine, and the health sciences. The center's core faculty manage their own research programs, conduct primary research in epidemiology and biostatistics, serve as members of collaborative research teams, manage cores and service centers that support research projects, and lead graduate training programs in epidemiology and biostatistics. The department provides an academic home and structure for faculty, provides primary research in epidemiology and biostatistics, supports the center's mission, and provides training in biostatistics. This organizational approach has wide applicability across schools of medicine in the United States and abroad and has been a model for many.

Objectives: To determine whether a rule-based algorithm applied to an outpatient electronic medical record (EMR) can identify patients who are pregnant and prescribed medications proved to cause birth defects., Design: A descriptive study using the University of Pennsylvania Health System outpatient EMR to simulate a prospective algorithm to identify exposures during pregnancy to category X medications, soon enough to intervene and potentially prevent the exposure. A subsequent post-hoc algorithm was also tested, working backwards from pregnancy endpoints, to search for possible exposures that should have been detected., Measurements: Category X medications prescribed to pregnant patients., Results: The alert simulation identified 2201 pregnancies with 16,969 pregnancy months (excluding abortions and ectopic pregnancies). Of these, 30 appeared to have an order for a non-hormone category X medication during pregnancy. However, none of the 30 'exposed pregnancies' were confirmed as true exposures in medical records review. The post-hoc algorithm identified 5841 pregnancies with 64 exposed pregnancies in 52,569 risk months, only one of which was a confirmed case., Conclusions: Category X medications may indeed be used in pregnancy, although rarely. However, most patients identified by the algorithm as exposed in pregnancy were not truly exposed. Therefore, implementing an electronic warning without evaluation would have inconvenienced prescribers, possibly hurting some patients (leading to non-use of needed drugs), with no benefit. These data demonstrate that computerized physician order entry interventions should be selected and evaluated carefully even before their use, using alert simulations such as that performed here, rather than just taken off the shelf and accepted as credible without formal evaluation.

Recent large--scale association studies, both of genome-wide and candidate gene design, have revealed several single-nucleotide polymorphisms (SNPs) which are significantly associated with risk of developing breast cancer. As both breast and endometrial cancers are considered to be hormonally driven and share multiple risk factors, we investigated whether breast cancer risk alleles are also associated with endometrial cancer risk. We genotyped nine breast cancer risk SNPs in up to 4188 endometrial cases and 11,928 controls, from between three and seven Caucasian populations. None of the tested SNPs showed significant evidence of association with risk of endometrial cancer.

Purpose: The Ziprasidone Observational study of car DIAC Outcomes (ZODIAC), a large simple trial comparing ziprasidone versus olanzapine in real-world use, showed no difference in risk of sudden death. Upon the request of the US Food and Drug Administration, 205 fatal events were readjudicated applying ICD-10 coding rules for sudden death., Methods: A readjudication committee coded three domains (witness to death, time of symptom onset to death, and most likely cause of death) for use within algorithms consistent with ICD-10 rules. Relative risks (RR) and corresponding 95%CI were calculated for persons randomized to ziprasidone versus olanzapine, comparing 1-year incidence of sudden death, using multiple definitions., Results: Data on symptom onset to death and diagnosis of specific cardiac arrhythmias required by the ICD-10 rules were often lacking. Sensitivity analyses were conducted to explore the impact of cases suggestive of cardiac origin but missing data required by ICD-10 sudden death codes. Overall, the readjudicated data matched the study's initial findings, with no significant difference in 1-year mortality between ziprasidone and olanzapine for sudden death not otherwise specified and sudden cardiac death (R96.0 or R96.1 or I46.1; RR = 1.11, 95%CI 0.45- 2.77)., Conclusions: After outcome readjudication, ZODIAC found no difference in the risk of sudden death among those randomized to ziprasidone versus olanzapine. However, unlike hospital-based studies, fatal events in general population studies often occur outside hospital and often lack the clinical detail needed for the exact determination of symptom onset and event. Epidemiological evaluations of sudden death need to consider the limitations of the available data., (Copyright © 2011 John Wiley & Sons, Ltd.)

Objective: The importance of adherence to aminoglycoside dosing recommendations by a pharmacokinetic monitoring service for preventing acute kidney injury (AKI) is unknown. We aimed to examine the association between AKI and discordance in aminoglycoside dosing between physician orders and recommendations by a pharmacokinetic monitoring service., Materials: We utilized 2000 - 2003 data from a large quaternary care academic medical center, including: hand-written pharmacokinetic monitoring service recommendations; computerized physician order entry inpatient medication orders; and electronic inpatient laboratory orders and results., Methods: We conducted a case-control study, nested within users of intravenous aminoglycosides. Outcomes of interest were cases of AKI, as determined by changes in serum creatinine. Exposures of interest were discordances between pharmacokinetic monitoring service recommendations and physician orders in the past 2 days with regard to total daily aminoglycoside dose., Results: Most patients received once-daily or less frequent aminoglycoside dosing. In 1,414 evaluable aminoglycoside courses, 220 patients developed AKI, for a cumulative incidence of 15.6%. We identified 690 controls, matched these to 220 cases, and found adjusted odds ratios of 0.72 (95% CI: 0.37 - 1.39) for overdose discordance and of 0.83 (0.51 - 1.34) for underdose discordance, suggesting that discordance in dosing is not associated with AKI., Conclusion: Non-adherence to dosing recommendations for aminoglycosides was not associated with risk of AKI in a setting primarily of once-daily aminoglycoside administration.

Background: The Health Improvement Network (THIN) database is a primary care electronic medical record database in the UK designed for pharmacoepidemiologic research. Matching on practice and calendar year often is used to account for secular trends in time and differences across practices. However, little is known about the consistency within practices across observation years and among practices within a given year, in THIN or other large medical record databases., Methods: We analyzed mortality rates, cancer incidence rates, prescribing rates, and encounter rates across 415 practices from 2000 to 2007 using a practice-year as the unit of observation in separate random and fixed effects longitudinal Poisson regression models. Adjusted models accounted for aggregate practice-level characteristics (smoking, obesity, age, and Vision software experience)., Results: In adjusted models, subsequent calendar years were associated with lower reported mortality rates, increasing cancer reporting rates, increasing prescriptions per patient, and decreasing encounters per patient, with a corresponding linear trend (p < 0.001 for all analyses). For calendar year 2007, the ratio of the 75th percentile to the 25th percentile for crude rate of cancer, mortality, prescriptions, and encounters was 1.63, 1.63, 1.45, and 1.42, respectively. Adjusting for practice characteristics reduced the among-practice variation by approximately 40%., Conclusions: THIN data are characterized by secular trends and among-practice variation, both of which should be considered in the design of pharmacoepidemiology studies. Whether these are trends in data quality or true secular trends could not be definitively differentiated., (Copyright © 2011 John Wiley & Sons, Ltd.)

Purpose: To evaluate the effect of obesity on survival among black women and white women with invasive breast cancer and to determine whether obesity explains the poorer survival of black women relative to white women., Patients and Methods: We observed 4,538 (1,604 black, 2,934 white) women who were 35 to 64 years of age when diagnosed with incident invasive breast cancer between 1994 and 1998. Multivariate Cox regression models were used to examine the effect of body mass index (BMI, in kilograms per square meter) 5 years before diagnosis on risk of death from any cause and from breast cancer., Results: During a median of 8.6 years of follow-up, 1,053 women died (519 black, 534 white), 828 as a result of breast cancer (412 black, 416 white). Black women were more likely to die than white women (multivariate-adjusted relative risk [RR], 1.33; 95% CI, 1.16 to 1.53). Compared with women with BMI of 20 to 24.9 kg/m(2), those who were obese (BMI ≥ 30 kg/m(2)) had a greater risk of all-cause mortality (RR, 1.23; 95% CI, 1.04 to 1.47) and breast cancer-specific mortality (RR, 1.20; 95% CI, 0.99 to 1.46). These associations were observed among white women (all-cause RR, 1.54; 95% CI, 1.21 to 1.96; breast cancer RR, 1.46; 95% CI, 1.11 to 1.92), but not among black women (all-cause RR, 1.03; 95% CI, 0.81 to 1.29; breast cancer RR, 1.02; 95% CI, 0.79 to 1.33)., Conclusion: Obesity may play an important role in mortality among white but not black patients with breast cancer. It is unlikely that differences in obesity distributions between black women and white women account for the poorer survival of black women.

Survey and detection programs for native and exotic forest insects frequently rely on traps baited with odorants, which mediate the orientation of target taxa (e.g., the southern pine beetle, Dendroctonusfrontalis Zimmermann) toward a resource (e.g., host material, mates). The influence of trap design on the capture efficiency of baited traps has received far less empirical attention than odorants, despite concerns that intercept traps currently used operationally have poor capture efficiencies for some target taxa (e.g., large woodborers). Several studies have recently demonstrated that treating traps with a surface lubricant to make them "slippery" can increase their capture efficiency; however, previously tested products can be expensive and their application time-consuming. The purpose of this study was to evaluate the effect of alternate, easier to apply aerosol lubricants on trap capture efficiency of selected forest insects. Aerosol formulations of Teflon and silicone lubricants increased both panel and multiple-funnel trap capture efficiencies. Multiple-funnel traps treated with either aerosol lubricant captured significantly more Monochamus spp. and Acanthocinus obsoletus (Olivier) than untreated traps. Similarly, treated panel traps captured significantly more Xylotrechus sagittatus (Germar), Ips calligraphus (Germar), Pissodes nemorensis (Germar), Monochamus spp., A. obsoletus, Thanasimus dubius (F.), and Ibalia leucospoides (Hochenwarth) than untreated traps. This study demonstrates that treating multiple-funnel and panel traps with an aerosol dry film lubricant can increase their capture efficiencies for large woodborers (e.g., Cerambycidae) as well as bark beetles, a weevil, a woodwasp parasitoid and a bark beetle natural enemy (Coleoptera: Cleridae).

Background: Oral contraceptives (OC) are widely used in the United States. Although the relation between OC use and breast cancer incidence has been widely studied, the few studies examining associations between OC use prior to breast cancer diagnosis and survival are inconsistent., Methods: Women with invasive breast cancer participating in the Women's Contraceptive and Reproductive Experiences (CARE) Study, a population-based case-control study (4565 women ages 35-64 years), and the California Teachers Study (CTS) cohort (3929 women ages 28-91 years) were followed for vital status. A total of 1,064 women died in the CARE Study (median follow-up, 8.6 years) and 523 died in the CTS (median follow-up, 6.1 years). Cox proportional hazards regression provided hazard rate ratio estimates [(relative risk, RR)] with 95% confidence intervals (CIs) for risk of death from any cause and from breast cancer., Results: No association was observed for any OC use prior to diagnosis and all-cause mortality [CARE Study: RR = 1.01 (95% CI = 0.86-1.19); CTS: RR = 0.84 (95% CI = 0.67-1.05)]. A decreased risk of all-cause mortality was observed in the CTS among women with more than 10 years of OC use (RR = 0.67, 95% CI = 0.47-0.96); however, no trend of decreasing risk with increasing OC duration was observed (P(trend) = 0.22), and no association was observed in the CARE study. No associations were observed for breast cancer-specific mortality., Conclusions: OC use is not associated with all-cause or breast cancer-specific mortality among women with invasive breast cancer., Impact: These 2 independent studies demonstrated no overall association between OC use and survival among women with breast cancer., (©2011 AACR)

Objective: The objective of this study was to compare the rate of severe cardiovascular events and death in children who use attention-deficit/hyperactivity disorder (ADHD) medications versus nonusers., Patients and Methods: We performed a large cohort study using data from 2 administrative databases. All children aged 3 to 17 years with a prescription for an amphetamine, atomoxetine, or methylphenidate were included and matched with up to 4 nonusers on the basis of data source, gender, state, and age. Cardiovascular events were validated using medical records. Proportional hazards regression was used to calculated hazard ratios., Results: We identified 241 417 incident users (primary cohort). No statistically significant difference between incident users and nonusers was observed in the rate of validated sudden death or ventricular arrhythmia (hazard ratio: 1.60 [95% confidence interval (CI): 0.19-13.60]) or all-cause death (hazard ratio: 0.76 [95% CI: 0.52-1.12]). None of the strokes identified during exposed time to ADHD medications were validated. No myocardial infarctions were identified in ADHD medication users. No statistically significant difference between prevalent users and nonusers (secondary cohort) was observed (hazard ratios for validated sudden death or ventricular arrhythmia: 1.43 [95% CI: 0.31-6.61]; stroke: 0.89 [95% CI: 0.11-7.11]; stroke/myocardial infarction: 0.72 [95% CI: 0.09-5.57]; and all-cause death: 0.77 [95% CI: 0.56-1.07)., Conclusions: The rate of cardiovascular events in exposed children was very low and in general no higher than that in unexposed control subjects. Because of the low number of events, we have limited ability to rule out relative increases in rate.

Objective: To explore whether treatment with pioglitazone was associated with risk of incident cancer at the 10 most common sites (prostate, female breast, lung/bronchus, endometrial, colon, non-Hodgkin lymphoma [NHL], pancreas, kidney/renal pelvis, rectal, and melanoma)., Research Design and Methods: A cohort study of 252,467 patients aged ≥40 years from the Kaiser Permanente Northern California Diabetes Registry was conducted. All prescriptions for diabetes medications were identified by pharmacy records. Cox proportional hazards models were used to examine the association between risk of incident cancer and ever use, duration, dose, and time since initiation of pioglitazone (modeled as time-dependent variables)., Results: In models adjusted for age, sex, year of cohort entry, race/ethnicity, income, smoking, glycemic control, diabetes duration, creatinine levels, congestive heart failure, and use of other diabetes medications, the hazard ratio (HR) for each cancer associated with ever use of pioglitazone ranged from 0.7 to 1.3, with all 95% CIs including 1.0. There was a suggestion of an increased risk of melanoma (HR 1.3 [95% CI 0.9-2.0]) and NHL (1.3 [1.0-1.8]) and a decreased risk of kidney/renal pelvis cancers (0.7 [0.4-1.1]) associated with ever use of pioglitazone. These associations were unaltered with increasing dose, duration, or time since first use., Conclusions: We found no clear evidence of an association between use of pioglitazone and risk of the incident cancers examined. Because the maximum duration of follow-up was fewer than 6 years after the initiation of pioglitazone, longer-term studies are needed.

Background: A 2005 report from the Centers for Medicare and Medicaid Services and the Centers for Disease Control Surgical Infection Prevention program indicated that only 41% of prophylactic antibacterials were correctly stopped within 24 h of the end of surgery. Electronic order sets have shown promise as a means of integrating guideline information with electronic order entry systems and facilitating safer, more effective care., Objective: The aim was to study the effectiveness of a computer-based antibacterial order set on increasing the proportion of patients who have antibacterial wound prophylaxis discontinued in the appropriate time frame., Design: The authors conducted a quasi-experimental interrupted time-series analysis over an 8-month study period with the implementation of a computer-based order system designed to prevent excessive duration of surgical prophylaxis antibacterials., Measurement: The primary outcome was the proportion of surgeries with antibacterials discontinued in the appropriate time frame. Additionally, we evaluated the percent of surgeries after implementation of the electronic intervention with chart documentation of infection among surgeries where the prescriber indicated the reason for antibacterial therapy was treatment., Results: The computer-based order intervention significantly improved the proportion of surgeries with timely discontinuation of antibacterials from 38.8% to 55.7% (p < 0.001) in the intervention hospital, while the control hospital remained at 56-57% (p = 0.006 for the difference between treated and control hospitals). In surgeries after intervention implementation where a prescriber indicated the reason for antibacterial therapy was treatment, the prevalence of chart documented infection was only 14%., Conclusions: A computer-based electronic order set intervention increased timely discontinuation of postoperative antibacterials.

In 2009 the federal government appropriated $34 billion in stimulus-related funding to promote the "meaningful use" of health information technology among Medicare and Medicaid providers and hospitals. One of the key elements of this technology is the adoption of computerized physician order entry (CPOE) systems for inpatient drug prescribing. The potential for CPOE to improve prescribing patterns and prevent adverse events is large, and as yet, unrealized. Amidst enthusiasm for the benefits of CPOE, providers and policymakers are becoming aware that CPOE could introduce new errors into the system and cannot simply be assumed to "work." This Issue Brief reports on the experience of one hospital system that used its CPOE to reduce the incidence of a serious drug interaction. This rigorous test of a specific CPOE intervention shows that an electronic alert system can be effective in changing prescribing, but may also have unintended consequences for patient safety.

Removal or impairment of ovaries before menopause may affect a woman's breast cancer risk by altering her cumulative exposure to ovarian hormones. The Women's Contraceptive and Reproductive Experiences Study, a population-based, multicenter case-control study of incident invasive breast cancer, recruited women aged 35-64 years (4,490 cases and 4,611 controls) who provided data on ovariectomy, hysterectomy, and tubal sterilization during in-person interviews. Controls were frequency-matched to cases by age, race, and study site. Unconditional logistic regression analysis was used. Women who had not undergone premenopausal reproductive surgery were the referent group. Bilateral ovariectomy was associated with reduced breast cancer risk overall (odds ratio (OR) = 0.59, 95% confidence interval (CI): 0.50, 0.69) and among women <45 years of age (ORs ranged from 0.31 to 0.52), but not among those who were older at surgery. It was also associated with a reduced risk for estrogen and progesterone receptor-positive tumors (OR = 0.63, 95% CI: 0.52, 0.75) but not receptor-negative tumors. Hysterectomy with ovarian conservation (OR = 0.83, 95% CI: 0.72, 0.96) and hysterectomy with partial ovary removal (OR = 0.73, 95% CI: 0.59, 0.91) were also associated with lower risk. No association with breast cancer risk was observed with tubal sterilization only or partial ovariectomy without hysterectomy. Reproductive organ surgeries may alter ovarian hormone levels, thereby affecting breast cancer risk.

Purpose: To describe the design and rationale of an investigator-initiated observational study to examine the cardiovascular safety of the following commonly-used medications to treat attention deficit hyperactivity disorder (ADHD): amphetamines, methylphenidate, and atomoxetine., Methods: We are conducting an observational cohort study using data from five large Medicaid programs and the HealthCore Integrated Research Database (HIRD(SM)), which is derived from administrative data from commercial health plans. Our primary outcomes of interest are (1) sudden death/ventricular arrhythmia, (2) stroke, (3) myocardial infarction, and (4) stroke or myocardial infarction as a composite outcome. These claims diagnoses have been previously validated in adults, and the positive predictive value in children will be examined as part of this study. Secondary outcomes are (1) all-cause death, (2) non-suicide death, and (3) non-accident death. All design decisions have been made to minimize bias toward the null. Based on our pilot data, we expect to have at least 90% power to detect a minimum detectable hazard ratio (HR) of 3.0 in children and adolescents who initiate an ADHD medication for each outcome of interest (except for MI, for which the expected minimum detectable HR is 7.9). The expected minimum detectable HR is 1.7 for each outcome for adult incident ADHD medication users., Results: Forthcoming., Conclusions: Potential limitations to this study include a low expected event rate in children and adolescents, potentially incomplete ascertainment of outcomes, and potential confounding by unmeasured variables. Nevertheless, this study will provide important information about the cardiovascular safety of ADHD medications., ((c) 2010 John Wiley & Sons, Ltd.)

Purpose: Some studies have reported reduced risks of advanced, but not early, prostate cancer among statin users, and one study found a reduced risk only among statin users who had also used non-steroidal anti-inflammatory drugs (NSAIDs). We have previously reported no association between statin use and prostate cancer in our hospital-based Case Control Surveillance Study. The purpose of the present analyses was to update the findings by cancer stage and to evaluate the joint use of statins and NSAIDs., Methods: Cases were 1367 men with prostate cancer and controls were 2007 men with diagnoses unrelated to statin or NSAID use. We used multivariable logistic regression analyses to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for statin use compared with no use, and joint use of statin and NSAIDs compared with use of neither., Results: The odds ratio among regular statin users was 1.1 (95%CI 0.9-1.5), and odds ratios were similar among early and late stage cancers. The odds ratio among joint statin and NSAID users was 1.1 (95%CI 0.7-1.6)., Conclusion: The present results do not support a protective effect of statin use, or statin and NSAID use, on the risk of advanced prostate cancer., ((c) 2010 John Wiley & Sons, Ltd.)

Background: Pain intensity is commonly reported using a 0-10 Numeric Rating Scale in pain clinical trials. Analysis of the change on the Pain Intensity Numerical Rating Scale as a proportion has most consistently correlated with clinically important differences reported on the patient's global impression of change. The correlation of data from patients with breakthrough pain with a Pain Relief Scale and a different global outcome measures will extend our understanding of these measures., Methods: Data were obtained from the open titration phase of a multiple crossover, randomized, double-blind clinical trial comparing oral transmucosal fentanyl citrate with immediate-release oral morphine sulfate for the treatment of cancer-related breakthrough pain. Raw and percentage changes in the pain intensity scores from 1,307 episodes of pain in 134 oral transmucosal fentanyl citrate-naïve patients were correlated with the clinically relevant secondary outcomes of Pain Relief Verbal Response Scale and the global medication performance scale. The changes in raw and percentage change were assessed over time and compared with the ordinal Pain Relief Verbal Response Scale and Global Medication Performance Scale., Results: The P value of the interaction between the raw pain intensity difference was significant (P = 0.034) for four 15-min time periods but not for the percentage pain intensity difference score (P = 0.26). We found similar results in comparison with the ordinal Pain Relief Verbal Response Scale (P = 0.0048 and P = 0.36 respectively) and global medication performance categories (P = 0.048 and P = 0.45, respectively)., Conclusion: The change in pain intensity in breakthrough pain was more consistent over time and when compared with both the Pain Relief Verbal Response Scale and the Global Medication Performance Scale when the percentage change is used rather than raw pain intensity difference.

Objective: Large body size has been associated with decreased risk of breast cancer in premenopausal women but with increased risk in postmenopausal women. Limited information is available about African-American women and differences by estrogen and progesterone receptor status., Methods: We analyzed data from the Women's Contraceptive and Reproductive Experiences Study among 3,997 white and African-American breast cancer case patients diagnosed in 1994 to 1998 and 4,041 control participants ages 35 to 64 years. We calculated multivariate odds ratios (OR) as measures of relative risk of breast cancer associated with self-reported body mass index (BMI) at age 18 and 5 years before diagnosis (recent BMI)., Results: Risk tended to decrease with increasing BMI at age 18 years in all women [OR(BMI > or = 25 kg/m(2) versus < 20 kg/m(2)) = 0.76; 95% confidence interval (CI), 0.63-0.90; P(trend) = 0.005] and with recent BMI in premenopausal women (OR(BMI > or = 35 kg/m(2) versus < 25 kg/m(2)) = 0.81; 95% CI, 0.61-1.06; P(trend) = 0.05), unmodified by race. Among postmenopausal white but not African-American women, there was an inverse relation between recent BMI and risk. High recent BMI was associated with increased risk of estrogen receptor- and progesterone receptor-positive tumors among postmenopausal African-American women (OR(BMI > or = 35 kg/m(2) versus < 25 kg/m(2)) = 1.83; 95% CI, 1.08-3.09; P(trend) = 0.03)., Conclusion: Among women at age 35 to 64 years, BMI at age 18 years is inversely associated with risk of breast cancer, but association with recent BMI varies by menopause status, race, and hormone receptor status., Impact: Our findings indicate that studies of BMI and breast cancer should consider breast cancer subtypes., (Copyright 2010 AACR.)

Purpose: Sudden cardiac death (SD) and ventricular arrhythmias (VAs) caused by medications have arisen as an important public health concern in recent years. The validity of diagnostic codes in identifying SD/VA events originating in the ambulatory setting is not well known. This study examined the positive predictive value (PPV) of hospitalization and emergency department encounter diagnoses in identifying SD/VA events originating in the outpatient setting., Methods: We selected random samples of hospitalizations and emergency department claims with principal or first-listed discharge diagnosis codes indicative of SD/VA in individuals contributing at least 6 months of baseline time within 1999-2002 Medicaid and Medicare data from five large states. We then obtained and reviewed medical records corresponding to these events to serve as the reference standard., Results: We identified 5239 inpatient and 29 135 emergency department events, randomly selected 100 of each, and obtained 119 medical records, 116 of which were for the requested courses of care. The PPVs for an outpatient-originating SD/VA precipitating hospitalization or emergency department treatment were 85.3% (95% confidence interval [CI] = 77.6-91.2) overall, 79.7% (95%CI = 68.3-88.4) for hospitalization claims, and 93.6% (95%CI = 82.5-98.7) for emergency department claims., Conclusions: First-listed SD/VA diagnostic codes identified in inpatient or emergency department encounters had very good agreement with clinical diagnoses and functioned well to identify outpatient-originating events. Researchers using such codes can be confident of the PPV when conducting studies of SD/VA originating in the outpatient setting.

Purpose: Among unanswered questions is whether menopausal use of estrogen therapy (ET) or estrogen-plus-progestin therapy (CHT) increases risk of developing fatal breast cancer i.e., developing and dying of breast cancer. Using a population-based case-control design, we estimated incidence rate ratios of fatal breast cancer in postmenopausal hormone therapy (HT) users compared to non-users by type, duration, and recency of HT use., Methods: HT use prior to breast cancer diagnosis in 278 women who died of breast cancer within 6 years of diagnosis (cases) was compared with use in 2224 controls never diagnosed with breast cancer using conditional logistic regression. Measures taken to address potential bias and confounding inherent in case-control studies included collecting and adjusting for detailed data on demographic and other factors potentially associated both with HT use and breast cancer., Results: Fifty-six per cent of cases and 68% of controls reported HT use. Among current 3+ year HT users, odds ratios and 95% confidence intervals for death were 0.83 (0.50, 1.38) and 0.69 (0.44, 1.09), respectively, for exclusive use of CHT or of ET, and were 0.94 (0.59, 1.48) and 0.70 (0.45, 1.07) for any use of CHT or of ET regardless of other hormone use., Conclusion: Point estimates suggest no increased risk of fatal breast cancer with HT use, although 50% increases in risk in longer-term current CHT users cannot be ruled out., ((c) 2010 John Wiley & Sons, Ltd.)

Findings from several previous studies that have assessed the relation of reproductive factors and female hormone use to the risk of pancreatic cancer are inconclusive. The authors examined the association between reproductive factors and the use of oral contraceptives and postmenopausal hormone therapy to the risk of pancreatic cancer among 284 patients with pancreatic cancer and 1,096 controls using data from the hospital-based Case-Control Surveillance Study. Older age at first pregnancy and long-duration oral contraceptive use were associated with an increased risk of pancreatic cancer: the odds ratio was 2.0 (95% CI: 1.1-3.3) for first birth at age 30 or older compared with before age 20 (p for trend = 0.042) and 2.0 (95% CI: 1.0-4.0) for ten or more years of use of oral contraceptive use relative to no-use (p for trend < 0.01). Risk of pancreatic cancer risk was not associated with postmenopausal female hormone use. The findings suggest that increased exposure to estrogen during the reproductive years may play a role in the development of pancreatic cancer in women. Further studies are needed to confirm the findings.

Background: Warfarin is an anticoagulant effective in preventing stroke, but it has a narrow therapeutic range requiring optimal adherence to achieve the most favorable effects., Purpose: The goal of this study was to examine specific patient factors that might help explain warfarin non-adherence at outpatient anticoagulation clinics., Method: In a prospective cohort study of 156 adults, we utilized logistic regression analyses to examine the relationship between the five Treatment Prognostics scales from the Millon Behavioral Medicine Diagnostic (MBMD), as well as three additional MBMD scales (Depression, Future Pessimism, and Social Isolation), and daily warfarin non-adherence assessed using electronic medication event monitoring systems caps over a median of 139 days., Results: Four of the five Treatment Prognostic scales and greater social isolation were associated with warfarin non-adherence. When controlling for pertinent demographic and medical variables, the Information Discomfort scale remained significantly associated with warfarin non-adherence over time., Conclusion: Although several factors were related to warfarin non-adherence, patients reporting a lack of receptivity to details regarding their medical illness seemed most at risk for warfarin non-adherence. This information might aid in the development of interventions to enhance warfarin adherence and perhaps reduce adverse medical events.

Epidemiologic studies suggest that some hormone-related risk factors in breast cancer differentially influence risk for disease subtypes classified by the status of the estrogen and progesterone receptors (ER/PR). However, it remains unclear whether human epidermal growth factor receptor 2 (HER2) or p53 expression status further differentiates these exposure-risk group associations. We evaluated the associations of oral contraceptive (OC) use and reproductive factors with incident invasive breast cancer subtypes among 1,197 population-based cases and 2,015 controls from the Los Angeles County or Detroit components of the Women's Contraceptive and Reproductive Experiences Study. Case-control comparisons by ER/PR/HER2/p53 status were conducted by multivariable polychotomous unconditional logistic regression methods. We found that OC use was not associated with any breast cancer subtype as defined by ER/PR/HER2/p53 status, except for a 2.9-fold increased risk of so-called triple-negative tumors (ER(-)/PR(-)/HER2(-)) among women of 45 to 64 years of age who started OC use before age 18. Parity was associated with a decreased risk of luminal A (ER(+) or PR(+), HER2(-)), luminal B (ER(+) or PR(+)/HER2(+)), and ER(-)/PR(-)/HER2(+) tumors. Age at first full-term pregnancy was positively associated with luminal A tumors among older women. Neither of these reproductive factors was associated with triple-negative tumors. Long duration of breast-feeding lowered the risk of triple-negative and luminal A tumors. p53 status did not define further differential risk patterns. Our findings offer evidence of differences in the hormone-related risk factors between triple-negative cancers and other ER/PR/HER2-defined subtypes of breast cancer.