Citations

Background— Atrial fibrillation (AF) often coexists with myocardial infarction (MI), yet its prognostic influence is disputed. Prior reports studied the relationship of AF during early hospitalization for acute MI to the risk of death and could not address the timing of AF in relation to the MI (ie, before, during, after). Furthermore, as data come mostly from clinical trials, their applicability to the community is uncertain. The aims of our study were to assess the occurrence of AF among MI patients, determine whether it has changed over time, and quantify its impact and the impact of its timing on mortality after MI. Methods and Results— This was a community-based cohort of 3220 patients hospitalized with incident (first-ever) MI from 1983 to 2007 in Olmsted County, MN. Atrial fibrillation was identified by diagnostic codes and ECG. Outcomes were all-cause and cardiovascular death. Atrial fibrillation before MI was identified in 304 patients, and 729 developed AF after MI (218 [30%] within 2 days, 119 [16%] between 3 and 30 days, and 392 [54%] >30 days post-MI). The cumulative incidence of AF after MI at 5 years was 19% and did not change over the calendar year of MI (the incidence of AF was the same regardless of when the MI occurred). During a mean follow-up of 6.6 years, 1638 deaths occurred. AF was associated with an increased risk of death (hazard ratio [95% confidence interval] 3.77 [3.37 to 4.21]), independently of clinical characteristics at the time of MI and heart failure. This risk differed markedly according to the timing of AF, and was the greatest for AF occurring >30 days post MI (hazard ratio [95% confidence interval] 1.63 [1.37 to 1.93] for AF within 2 days, 1.81 [0.45 to 2.27] for AF between 3 and 30 days, and 2.58 [2.21 to 3.00] for AF >30 days post MI). Conclusions— In the community, AF is frequent in the setting of MI. Atrial fibrillation carries an excess risk of death, which is the highest for AF developing >30 days after MI.

The goal of health care is to provide high-quality care at an affordable cost for its patients. However, the population it serves has changed dramatically since the popularization of hospital-based health care. With available new technology, alternative health care delivery methods can be designed and tested. This study examines scalable office-based health care for small business, where health care is delivered to the office floor. This delivery was tested in 18 individuals at a small business in Minneapolis, Minnesota. The goal was to deliver modular health care and mitigate conditions such as diabetes, hyperlipidaemia, obesity, sedentariness and metabolic disease. The modular health care system was welcomed by employees – 70% of those eligible enrolled. The findings showed that the modular health care deliverable was feasible and effective. The data demonstrated significant improvements in weight loss, fat loss and blood variables for at risk participants. This study leaves room for improvement and further innovation. Expansion to include offerings such as physicals, diabetes management, smoking cessation and prenatal treatment would improve its utility. Future studies could include testing the adaptability of delivery method, as it should adapt to reach rural and under-served populations.

Purpose Patients with inflammatory breast cancer (IBC) or locally advanced breast cancer (LABC) were randomly assigned to 21-day doxorubicin and cyclophosphamide administered for five cycles (standard arm) versus weekly doxorubicin and daily oral cyclophosphamide administered with granulocyte colony-stimulating factor support for 15 weeks (continuous arm). All patients had subsequent weekly paclitaxel for 12 weeks before surgery. Patients and Methods Patients (n = 372) were randomly assigned to the standard arm (n = 186) or the continuous arm (n = 186) stratified by disease type (LABC, n = 256; IBC, n = 116). The primary outcome was microscopic pathologic complete response (pCR) at surgery. Secondary outcomes included disease-free survival, overall survival, and toxicity. Results More patients in the standard arm had grade 3 to 4 leukopenia and neutropenia, but there were more instances of stomatitis/pharyngitis and hand-foot skin reaction in the continuous arm. Assessed among 356 eligible patients, pCR was not different between the treatment groups stratified by disease type (P = .42). In subset analysis, higher pCR rates were observed in the continuous arm versus the standard arm only for stage IIIB disease (P = .0057) and in IBC (P = .06). Comparison of overall survival and disease-free survival showed no difference between treatment groups (P = .37 and P = .87, respectively). Conclusion No significant clinical benefit was seen for the investigational arm in this trial overall.

Abstract Background: Taxane-induced peripheral neuropathy is a dose-limiting side effect that leads to suboptimal cancer treatment and diminished quality of life. The mode of taxane neurotoxicity is unclear, but may be through stabilization of microtubules and induction of spindle checkpoint, leading to cell cycle arrest at G2/M. Fanconi Anemia (FA) genes, including FANCD2, and FANCA, appear to be involved in G2/M phase checkpoint maintenance as well as spindle checkpoint in response to internal and external signals, such as taxane treatment. Thus, we hypothesized that variants in FA genes could impact severity of taxane-induced neuropathies.Methods: Using DNA extracted from blood collected from 893 breast cancer patients participating in a trial evaluating metronomic dosing of cyclophosphamide, doxorubicin and paclitaxel (S0221), we genotyped for single nucleotide polymorphisms (SNPs) that represent all of the variability across FANCA (44 SNPs) and FANCD2 (24 SNPs) in all race/ethnicity groups, as well as a panel of ancestry informative markers to control for potential population stratification, using Illumina GoldenGate platform. SNPs with minor allele frequency (MAF) less than 0.10 and those out of Hardy Weinberg Equilibrium (HWE) proportions (p<0.001) were removed from analyses. Ordinal regression was used to test for allelic and haplotypic association with grade 3 or 4 toxicities relative to 0, 1, and 2 toxicities, adjusting for age, genetic admixture index and treatment arm. To adjust for multiple testing, permutation analyses were performed on both single SNP and haplotype models.Results: Eighteen SNPs in FANCD2 and 38 SNPs in FANCA passed MAF and HWE proportion requirements. For FANCD2, 4 SNPs spanning 67.5 Kb (rs7648104, rs2272125 [coding SNP], rs6786638 and rs644215), were significantly associated with taxane-induced neuropathy (p<0.001) after controlling for multiple testing, with each SNP resulting in approximately a twofold increase in odds of severe taxane-induced neuropathy. Haplotype estimation showed that all 18 SNPs comprise a single haplotype. Two major (>1% frequency) haplotypes were found. The frequencies of the risk haplotype in cases (patients with grade 3 or 4 neuropathy) and controls (patients with ≤ grade 2 neuropathy) were 0.25 and 0.15, respectively. Ordinal regression analyses were highly significant (p<0.0005); patients with at least one copy of the risk haplotype had more than a twofold increased risk of grade 3 or 4 taxane-induced neuropathy (OR=2.2, 95% CI 1.44, 3.44). For FANCA, no SNPs or haplotypes were significantly associated with grade 3 or 4 neurotoxicity, either prior to or after correction for multiple testing.Conclusions: These results indicate that the Fanconi-Anemia pathway may be important for neurological sensitivity to taxanes, and that genotypic markers might be able to be used to identify patients at increased risk for severe taxane-induced neuropathy. Further studies will elucidate potential associations with survival outcomes. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2001.

A session about educating translational scientists was held at a 2010 NIH forum on promoting collaborations between academia, government, and industry.

Background— Studies report a protective effect of higher attained educational level (AEL) on cardiovascular outcomes. However, most of these studies have been conducted in high-income countries (HICs) and lack representation from low- and middle-income countries (LMICs), which bear >80% of the global burden of cardiovascular disease. Methods and Results— The Reduction of Atherothrombosis for Continued Health (REACH) Registry is a prospective study of 67 888 subjects with either established atherothrombotic (coronary, cerebrovascular, and/or peripheral arterial) disease or multiple atherothrombotic risk factors enrolled from 5587 physician practices in 44 countries. At baseline, AEL (0 to 8 years, 9 to 12 years, trade or technical school, and university) was self-reported for 61 332 subjects. Outcomes included the baseline prevalence of atherothrombotic risk factors and the rate of incident cardiovascular events (cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke) through 23 months across AEL groups, stratified by sex and world region (LMICs or HICs). Educational attainment was inversely associated with age and diabetes mellitus and directly associated with hypercholesterolemia in all subjects. However, for other risk factors such as obesity, smoking, hypertension, and baseline burden of vascular disease, AEL was protective (inversely associated) in HICs but not protective in LMICs. The protective effect of greater AEL on incident cardiovascular events was strongest in men from HICs ( P <0.0001), more modest in women from HICs ( P =0.0026) and in men from LMICs ( P =0.082), and essentially absent in women from LMICs ( P =0.32). Conclusion— In contrast to HICs, higher AEL may not be protective against cardiovascular events in LMICs, particularly in women.

Background and Purpose— In clinical trials and observational studies there is considerable inconsistency in the use of definitions to describe delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage. A major cause for this inconsistency is the combining of radiographic evidence of vasospasm with clinical features of cerebral ischemia, although multiple factors may contribute to DCI. The second issue is the variability and overlap of terms used to describe each phenomenon. This makes comparisons among studies difficult. Methods— An international ad hoc panel of experts involved in subarachnoid hemorrhage research developed and proposed a definition of DCI to be used as an outcome measure in clinical trials and observational studies. We used a consensus-building approach. Results— It is proposed that in observational studies and clinical trials aiming to investigate strategies to prevent DCI, the 2 main outcome measures should be: (1) cerebral infarction identified on CT or MRI or proven at autopsy, after exclusion of procedure-related infarctions; and (2) functional outcome. Secondary outcome measure should be clinical deterioration caused by DCI, after exclusion of other potential causes of clinical deterioration. Vasospasm on angiography or transcranial Doppler can also be used as an outcome measure to investigate proof of concept but should be interpreted in conjunction with DCI or functional outcome. Conclusion— The proposed measures reflect the most relevant morphological and clinical features of DCI without regard to pathogenesis to be used as an outcome measure in clinical trials and observational studies.

Abstract The advent of improved biomarkers promises to enhance the clinical care for patients with rheumatoid arthritis (RA) and other immune-mediated disorders. We have developed an innovative approach to broadly assess the cytokine responsiveness of human PBMCs using a multistimulant panel and multiplexed immunoassays. The objective of this study was to demonstrate this concept by determining whether cytokine profiles could discriminate RA patients according to disease stage (early versus late) or severity. A 10-cytokine profile, consisting of IL-12, CCL4, TNF-α, IL-4, and IL-10 release in response to stimulation with anti-CD3/anti-CD28, CXCL8 and IL-6 in response to CMV and EBV lysate, and IL-17A, GM-CSF, and CCL2 in response to human heat shock protein 60, easily discriminated the early RA group from controls. These data were used to create an immune response score, which performed well in distinguishing the early RA patients from controls and also correlated with several markers of disease severity among the patients with late RA. In contrast, the same 10-cytokine profile assessed in serum was far less effective in discriminating the groups. Thus, our approach lays the foundation for the development of immunologic “signatures” that could be useful in predicting disease course and monitoring the outcomes of therapy among patients with immune-mediated diseases.

Background. Patients’ values are fundamental to decision models, cost-effectiveness analyses, and pharmacoeconomic analyses. The standard methods used to assess how patients value different health states are inherently quantitative. People without strong quantitative skills (i.e., low numeracy) may not be able to complete these tasks in a meaningful way. Methods. To determine whether the validity of utility assessments depends on the respondent’s level of numeracy, the authors conducted in-person interviews and written surveys and assessed utility for the current health for 96 women volunteers. Numeracy was measured using a previously validated 3-item scale. The authors examined the correlation between self-reported health and utility for current health (assessed using the standard gamble, time trade-off, and visual analog techniques) across levels of numeracy. For half of the women, the authors also assessed standard gamble utility for 3 imagined health states (breast cancer, heart disease, and osteoporosis) and asked how much the women feared each disease. Results. Respondent ages ranged from 50 to 79 years (mean = 63), all were high school graduates, and 52% had a college or postgraduate degree. Twenty-six percent answered 0 or only 1 of the numeracy questions correctly, 37% answered 2 correctly, and 37% answered all 3 correctly. Among women with the lowest level of numeracy, the correlation between utility for current health and self-reported health was in the wrong direction (i.e., worse health valued higher than better health): for standard gamble, Spearman r = -0.16, P =0.44; for time trade-off, Spearman r = -0.13, P = 0.54. Among the most numerate women, the authors observed a fair to moderate positive correlation with both standard gamble (Spearman r = 0.22, P = 0.19) and time trade-off (Spearman r = 0.50, P = 0.002). In contrast, using the visual analog scale, the authors observed a substantial correlation in the expected direction at all levels of numeracy (Spearman r =0.82, 0.50, and 0.60 for women answering 0-1, 2, and 3 numeracy questions, respectively; all P s ≤ 0.003). With regard to the imagined health states, the most feared disease had the lowest utility for 35% of the women with the lowest numeracy compared to 76% of the women with the highest numeracy (P = 0.03). Conclusions. The validity of standard utility assessments is related to the subject’s facility with numbers. Limited numeracy may be an important barrier to meaningfully assessing patients’ values using the standard gamble and time trade-off techniques.