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Thomas Helland;
Nina Henne;
Ersilia Bifulco;
Bjorn Naume;
ELin Borgen;
Vessela N. Kristensen;
Jan T. Kvaloy;
Timothy Lash;
Grethe I. G. Alns;
Ron H. van Schaik;
Emiel A. M. Janssen;
Steinar Hustad;
Ernst A. Lien;
Gunnar Mellgren;
Havard Soiland
Background: Controversies exist as to whether the genetic polymorphisms of the enzymes responsible for the metabolism of tamoxifen can predict breast cancer outcome in patients using adjuvant tamoxifen. Direct measurement of concentrations of active tamoxifen metabolites in serum may be a more biological plausible and robust approach. We have investigated the association between CYP2D6 genotypes, serum concentrations of active tamoxifen metabolites, and long-term outcome in tamoxifen treated breast cancer patients. Methods: From an original observational study comprising 817 breast cancer patients, 99 women with operable breast cancer were retrospectively included in the present study. This cohort of patients were adjuvantly treated with tamoxifen, had provided serum samples suitable for measuring tamoxifen metabolites, and were relapse-free at 3 years after the primary treatment commenced. The median follow-up time from this entry point to breast cancer death was 13.9 years. Patients were CYP2D6 genotyped and grouped into four CYP2D6 phenotype groups (Ultra rapid, extensive, intermediate, and poor metabolizers). Tamoxifen and nine metabolites were quantified in serum (n = 86) and compared with CYP2D6 phenotype groups and outcome. Results: Breast cancer patients with low concentrations of Z-4-hydroxy-tamoxifen (Z-4OHtam; ≤ 3.26 nM) had a breast cancer-specific survival (BCSS) of 60% compared to 84% in patients with Z-4OHtam concentrations > 3.26 nM (p = 0.020, log-rank hazard ratio (HR) = 3.56, 95% confidence interval (CI) = 1.14-11.07). For patients with Z-4-hydroxy-N-desmethyl-tamoxifen (Z-endoxifen) levels ≤ 9.00 nM BCSS was 57% compared to 84% for patients with concentrations > 9.00 nM (p = 0.029, HR = 3.73, 95% CI = 1.05-13.22). Low concentrations of Z-4OHtam and Z-endoxifen were associated with poorer survival also after adjusting for clinically relevant variables (HR = 4.27, 95% CI = 1.35-13.58, and HR = 3.70, 95% CI = 1.03-13.25, respectively). Overall survival analysis showed similar survival differences for both active metabolites. The Antiestrogen Activity Score showed comparable effects, but did not improve the prognostic information. Conclusions: Patients with Z-4OHtam and Z-endoxifen concentrations lower than 3.26 nM or 9.00 nM, respectively, showed an adverse outcome. Our results suggest that direct measurement of active tamoxifen metabolite concentrations could be of clinical value. Validation in larger study cohorts is warranted.
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Julie A. Womack;
Terrence E. Murphy;
Harini Bathulapalli;
Kathleen M. Akgun;
Cynthia Gibert;
Ken M. Kunisaki;
David Rimland;
Maria Rodriguez-Barradas;
H. Klar Yaggi;
Amy C. Justice;
Nancy S. Redeker
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Akira Fujiyoshi;
David R. Jacobs;
Annette L. Fitzpatrick;
Alvaro Alonso;
Daniel A. Duprez;
A. Richey Sharrett;
Teresa Seeman;
Michael J. Blaha;
Jose A. Luchsinger;
Stephen R. Rapp
Background-Studies suggest a link between vascular injuries and dementia. Only a few studies, however, examined a longitudinal relation of subclinical vascular disease with dementia. We tested whether baseline coronary artery calcium (CAC), a biomarker of subclinical vascular disease, is associated with incident dementia independent of vascular risk factors and APOE-e4 genotype in a community-based sample. Methods and Results-We analyzed 6293 participants of MESA (Multi-Ethnic Study of Atherosclerosis), aged 45 to 84 years at baseline (2000-2002), initially free of cardiovascular disease and noticeable cognitive deficit. Dementia cases were identified using hospital and death certificate International Statistical Classification of Diseases and Related Health Problems codes. Cox models were used to obtain hazard ratios according to CAC category, or per 1 SD log2[CAC+1], adjusted for vascular risk factor, APOE-e4, with or without exclusion of interim stroke or cardiovascular disease. We observed 271 dementia cases in a median follow-up of 12.2 years. Baseline CAC had a graded positive association with dementia risk. Compared with no CAC, CAC score of 1 to 400, 401 to 1000, and =1001 had increased risk of dementia by 23%, 35%, and 71%, respectively, (Ptrend=0.026) after adjustment. 1 SD higher log2[CAC+1] was associated with 24% (95% confidence interval, 8%-41%; P=0.002) increase in dementia risk. Although the association was partially explained by interim stroke/cardiovascular disease, it remained significant even after excluding the interim events, or regardless of baseline age. Conclusions-Higher baseline CAC was significantly associated with increased risk of dementia independent of vascular risk factor, APOE-e4, and incident stroke. This is consistent with a hypothesis that vascular injuries play a role in the development of dementia.
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Emir Veledar;
Suephy Chen;
Christina M. Correnti;
David J. Klein;
Marc N. Elliott;
Mona Saraiya;
Alyna T. Chien;
David C. Schwebel;
Sylvie Mrug;
Susan R. Tortolero;
Paula M. Cuccaro;
Mark A. Schuster
Background/Objectives: Despite rising skin cancer rates in children, multiple studies reveal inadequate youth sun-protective behavior (eg, sunscreen use). Using Healthy Passages data for fifth-graders, we set out to determine sunscreen adherence in these children and investigated factors related to sunscreen performance.
Methods: Survey data were collected from 5119 fifth-graders and their primary caregivers. Logistic regression was used to assess associations between sunscreen adherence and performance of other preventive health behaviors (eg, flossing, helmet use) and examine predictors of sunscreen adherence. Analyses were repeated in non-Hispanic black, Hispanic, and non-Hispanic white subgroups.
Results: Five thousand one hundred nineteen (23.4%) children almost always used sunscreen, 5.9% of non-Hispanic blacks (n = 1748), 23.7% of Hispanics (n = 1802), and 44.8% of non-Hispanic whites (n = 1249). Performing other preventive health behaviors was associated with higher odds of sunscreen adherence (all P <.001), with the greatest association with flossing teeth (odds ratio = 2.41, 95% confidence interval = 1.86-3.13, P <.001). Factors for lower odds of sunscreen adherence included being male and non-Hispanic black or Hispanic and having lower socioeconomic status. School-based sun-safety education and involvement in team sports were not significant factors.
Conclusion: Our data confirm low use of sun protection among fifth-graders. Future research should explore how public health success in increasing prevalence of other preventive health behaviors may be applied to enhance sun protection messages. Identifying risk factors for poor adherence enables providers to target patients who need more education. Improving educational policies and content in schools may be an effective way to address sun safety.
Introduction A substantial share of urban Indians with diagnosed hypertension do not take regular treatment, potentially due to poor knowledge of hypertension consequences and treatment options. We describe hypertension knowledge and beliefs, treatment patterns, and reported reasons for treatment non-use among adults with diagnosed hypertension in Chennai, India. Methods We collected data on 833 adults ages 30+ with physician diagnosed hypertension using a door-to-door household survey within randomly selected wards of Chennai. We described the proportion of individuals who were not taking daily medications and their reported reasons for not doing so. Next, we described individuals' knowledge of hypertension consequences and how to control blood pressure (BP) and assessed the association between knowledge and daily treatment use. Results Over one quarter (28% (95% CI 25% to 31%)) of diagnosed individuals reported not taking daily treatment. The largest proportion (18% (95% CI 16% to 21%)) were individuals who had discontinued prior treatment use. The primary reason individuals reported for non-daily use was that their BP had returned to normal. Just 23% (95% CI 20% to 26%) of individuals listed BP medications as the most effective way to reduce BP; however, these individuals were 11% points (95% CI 4% to 19%) more likely to take daily medications. Conversely, 43% (95% CI 40% to 47%) of individuals believed that BP medications should be stopped from time to time and these individuals were 15% points (95% CI -0.21 to -0.09) less likely to take daily treatment. While awareness of the consequences of hypertension was poor, we found no evidence that it was associated with taking daily medications. Conclusions There were large gaps in consistency of BP medication use which were strongly associated with knowledge about BP medications. Further research is needed to identify whether addressing beliefs can improve daily treatment use among individuals with diagnosed hypertension.
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Lotte Kaasenbrood;
Deepak L. Bhatt;
Jannick A. N. Dorresteijn;
Peter Wilson;
Ralph B. D'Agostino;
Joseph M. Massaro;
Yolanda van der Graaf;
Maarten J. M. Cramer;
L. Jaap Kappelle;
Gert J. de Borst;
Ph. Gabriel Steg;
Frank L. J. Visseren
Background-In patients with vascular disease, risk models may support decision making on novel risk reducing interventions, such as proprotein convertase subtilisin/kexin type 9 inhibitors or anti-inflammatory agents. We developed and validated an innovative model to estimate life expectancy without recurrent cardiovascular events for individuals with coronary, cerebrovascular, and/or peripheral artery disease that enables estimation of preventive treatment effect in lifetime gained. Methods and Results-Study participants originated from prospective cohort studies: the SMART (Secondary Manifestations of Arterial Disease) cohort and REACH (Reduction of Atherothrombosis for Continued Health) cohorts of 14 259 (REACH Western Europe), 19 170 (REACH North America) and 6959 (SMART, The Netherlands) patients with cardiovascular disease. The SMARTREACH model to estimate life expectancy without recurrent events was developed in REACH Western Europe as a Fine and Gray competing risk model incorporating cardiovascular risk factors. Validation was performed in REACH North America and SMART. Outcomes were (1) cardiovascular events (myocardial infarction, stroke, cardiovascular death) and (2) noncardiovascular death. Predictors were sex, smoking, diabetes mellitus, systolic blood pressure, total cholesterol, creatinine, number of cardiovascular disease locations, atrial fibrillation, and heart failure. Calibration plots showed high agreement between estimated and observed prognosis in SMART and REACH North America. C-statistics were 0.68 (95% confidence interval, 0.67-0.70) in SMART and 0.67 (95% confidence interval, 0.66-0.68) in REACH North America. Performance of the SMART-REACH model was better compared with existing risk scores and adds the possibility of estimating lifetime gained by novel therapies. Conclusions-The externally validated SMART-REACH model could be used for estimation of anticipated improvements in life expectancy without recurrent cardiovascular events in individual patients with cardiovascular disease in Western Europe and North America.
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Sridharan Raghavan;
Yuk-Lam Ho;
Jason L Vassy;
Daniel Posner;
Jacqueline Honerlaw;
Lauren Costa;
Lawrence Phillips;
David R Gagnon;
Peter Wilson;
Kelly Cho
Background: Estimated 10-year atherosclerotic cardiovascular disease (ASCVD) risk in diabetes mellitus patients is used to guide primary prevention, but the performance of risk estimators (2013 Pooled Cohort Equations [PCE] and Risk Equations for Complications of Diabetes [RECODe]) varies across populations. Data from electronic health records could be used to improve risk estimation for a health system's patients. We aimed to evaluate risk equations for initial ASCVD events in US veterans with diabetes mellitus and improve model performance in this population. Methods AND RESULTS: We studied 183 096 adults with diabetes mellitus and without prior ASCVD who received care in the Veterans Affairs Healthcare System (VA) from 2002 to 2016 with mean follow-up of 4.6 years. We evaluated model discrimination, using Harrell's C statistic, and calibration, using the reclassification χ2test, of the PCE and RECODe equations to predict fatal or nonfatal myocardial infarction or stroke and cardiovascular mortality. We then tested whether model performance was affected by deriving VA-specific β-coefficients. Discrimination of ASCVD events by the PCE was improved by deriving VA-specific β-coefficients (C statistic increased from 0.560 to 0.597) and improved further by including measures of glycemia, renal function, and diabetes mellitus treatment (C statistic, 0.632). Discrimination by the RECODe equations was improved by substituting VA-specific coefficients (C statistic increased from 0.604 to 0.621). Absolute risk estimation by PCE and RECODe equations also improved with VA-specific coefficients; the calibration P increased from <0.001 to 0.08 for PCE and from <0.001 to 0.005 for RECODe, where higher P indicates better calibration. Approximately two-thirds of veterans would meet a guideline indication for high-intensity statin therapy based on the PCE versus only 10% to 15% using VA-fitted models. Conclusions: Existing ASCVD risk equations overestimate risk in veterans with diabetes mellitus, potentially impacting guideline-indicated statin therapy. Prediction model performance can be improved for a health system's patients using readily available electronic health record data.