Emory Clinic

Socioeconomic status (SES) has a measurable and significant effect on cardiovascular health. Biological, behavioral, and psychosocial risk factors prevalent in disadvantaged individuals accentuate the link between SES and cardiovascular disease (CVD). Four measures have been consistently associated with CVD in high-income countries: income level, educational attainment, employment status, and neighborhood socioeconomic factors. In addition, disparities based on sex have been shown in several studies. Interventions targeting patients with low SES have predominantly focused on modification of traditional CVD risk factors. Promising approaches are emerging that can be implemented on an individual, community, or population basis to reduce disparities in outcomes. Structured physical activity has demonstrated effectiveness in low-SES populations, and geomapping may be used to identify targets for large-scale programs. Task shifting, the redistribution of healthcare management from physician to nonphysician providers in an effort to improve access to health care, may have a role in select areas. Integration of SES into the traditional CVD risk prediction models may allow improved management of individuals with high risk, but cultural and regional differences in SES make generalized implementation challenging. Future research is required to better understand the underlying mechanisms of CVD risk that affect individuals of low SES and to determine effective interventions for patients with high risk. We review the current state of knowledge on the impact of SES on the incidence, treatment, and outcomes of CVD in high-income societies and suggest future research directions aimed at the elimination of these adverse factors, and the integration of measures of SES into the customization of cardiovascular treatment.

It is essential that there be consistency in the conduct, analysis, and reporting of clinical trial results in myeloma. The goal of the International Myeloma Workshop Consensus Panel 1 was to develop a set of guidelines for the uniform reporting of clinical trial results in myeloma. This paper provides a summary of the current response criteria in myeloma, detailed definitions for patient populations, lines of therapy, and specific endpoints. We propose that future clinical trials in myeloma follow the guidelines for reporting results proposed in this manuscript.

BACKGROUND: Computer-aided detection identifies suspicious findings on mammograms to assist radiologists. Since the Food and Drug Administration approved the technology in 1998, it has been disseminated into practice, but its effect on the accuracy of interpretation is unclear. METHODS: We determined the association between the use of computer-aided detection at mammography facilities and the performance of screening mammography from 1998 through 2002 at 43 facilities in three states. We had complete data for 222,135 women (a total of 429,345 mammograms), including 2351 women who received a diagnosis of breast cancer within 1 year after screening. We calculated the specificity, sensitivity, and positive predictive value of screening mammography with and without computer-aided detection, as well as the rates of biopsy and breast-cancer detection and the overall accuracy, measured as the area under the receiver-operating-characteristic (ROC) curve. RESULTS: Seven facilities (16%) implemented computer-aided detection during the study period. Diagnostic specificity decreased from 90.2% before implementation to 87.2% after implementation (P<0.001), the positive predictive value decreased from 4.1% to 3.2% (P=0.01), and the rate of biopsy increased by 19.7% (P<0.001). The increase in sensitivity from 80.4% before implementation of computer-aided detection to 84.0% after implementation was not significant (P=0.32). The change in the cancer-detection rate (including invasive breast cancers and ductal carcinomas in situ) was not significant (4.15 cases per 1000 screening mammograms before implementation and 4.20 cases after implementation, P=0.90). Analyses of data from all 43 facilities showed that the use of computer-aided detection was associated with significantly lower overall accuracy than was nonuse (area under the ROC curve, 0.871 vs. 0.919; P=0.005). CONCLUSIONS: The use of computer-aided detection is associated with reduced accuracy of interpretation of screening mammograms. The increased rate of biopsy with the use of computer-aided detection is not clearly associated with improved detection of invasive breast cancer.

CONTEXT: Inappropriate medication use is a major patient safety concern, especially for the elderly population. Using explicit criteria, prior studies have found that 23.5% and 17.5% of the US community-dwelling elderly population used at least 1 of 20 potentially inappropriate medications in 1987 and 1992, respectively. OBJECTIVES: To determine the prevalence of potentially inappropriate medication use in community-dwelling elderly persons in 1996, to assess trends over 10 years, categorize inappropriate medication use according to explicit criteria, and to examine risk factors for inappropriate medication use. DESIGN, SETTING, AND PARTICIPANTS: Respondents aged 65 years or older (n = 2455) to the 1996 Medical Expenditure Panel Survey, a nationally representative survey of the US noninstitutionalized population were included. A 7-member expert panel was convened to categorize inappropriate medications. MAIN OUTCOME MEASURE: Prevalence of use of 33 potentially inappropriate medications. RESULTS: In 1996, 21.3% (95% confidence interval [CI], 19.5%-23.1%) of community-dwelling elderly patients in the United States received at least 1 of 33 potentially inappropriate medications. Using the expert panel's classifications, about 2.6% of elderly patients (95% CI, 2.0%-3.2%) used at least 1 of the 11 medications that should always be avoided by elderly patients; 9.1% (95% CI, 7.9%-10.3%) used at least 1 of the 8 that would rarely be appropriate; and 13.3% (95% CI, 11.7%-14.9%) used at least 1 of the 14 medications that have some indications but are often misused. Use of some inappropriate medications declined between 1987 and 1996. Persons with poor health and more prescriptions had a significantly higher risk of inappropriate medication use. CONCLUSIONS: Overall inappropriate medication use in elderly patients remains a serious problem. Despite challenges in using explicit criteria for assessing inappropriate medications for elderly patients, such criteria can be applied to population-based surveys to identify opportunities to improve quality of care and patient safety. Enhancements of existing data sources to include dosage, duration, and indication may augment national improvement and monitoring efforts.

BACKGROUND: The Global Utilization of Streptokinase and TPA for Occluded Coronary Arteries (GUSTO-I) trial was designed to test whether thrombolytic strategies achieving more complete, early, sustained coronary artery patency would lead to further reductions in mortality in patients with acute myocardial infarction. An angiographic substudy within GUSTO-I provided a unique opportunity to examine the relation between mortality and degrees of patency among the regimens. METHODS AND RESULTS: Four thrombolytic strategies were compared in 41,021 patients in GUSTO-I: streptokinase with subcutaneous or intravenous heparin, accelerated tissue plasminogen activator (TPA) with intravenous heparin, and combination streptokinase plus TPA with intravenous heparin. Accelerated TPA was associated with lower 30-day mortality (6.3%) than the other strategies (7.2%, 7.4%, and 7.0%, respectively). Among the 1210 patients in the angiographic substudy randomized to angiography 90 minutes after starting treatment, there was improved patency, particularly Thrombolysis in Myocardial Infarction (TIMI) grade 3 flow, with accelerated TPA over the other regimens (P < .0001). Coronary artery perfusion (TIMI grade 3) at 90 minutes was also a significant predictor of 30-day survival (P < .01). To determine whether differences in mortality among the four strategies matched differences in 90-minute patency, a model was developed for predicting mortality differences in the main trial from the angiographic substudy. The model assumed that any differences in treatment effects on 30-day mortality were mediated through differences in 90-minute patency for the four treatments. The predicted rates were then compared with observed mortality rates of the remaining patients in the main trial for each treatment group. The predicted and observed 30-day mortality rates of the four treatments were streptokinase with subcutaneous heparin, 7.46% versus 7.28%; streptokinase with intravenous heparin, 7.26% versus 7.39%; accelerated TPA, 6.31% versus 6.37%; and streptokinase plus TPA, 6.98% versus 6.96%. The correlation between predicted and observed results was .97, and the proportion of squared error explained (R2) was .92. CONCLUSIONS: The close relation between the predicted and observed 30-day mortality rates supports the concept that an important mechanism for improved survival with thrombolytic therapy is achievement of early, complete perfusion. The close match provides a strong biological explanation for the mortality differences seen in GUSTO-I and a sound rationale for the additional survival advantage of the accelerated TPA regimen. Irrespective of which treatment is used, early and complete restoration of infarct artery perfusion represents an essential goal of myocardial reperfusion therapy.

To explore the relationship between surgical approach and chronic posterior iliac crest donor site pain, 151 bone graft harvests with follow-up periods longer than 1 year were evaluated using a detailed questionnaire and follow-up clinical visits. There was no difference in the incidence of chronic donor site pain between harvests performed through the primary midline incision versus a separate lateral oblique incision (28 vs 31%). Twice as many donor sites harvested for reconstructive spinal procedures were reported as having chronic pain as compared with those harvested for spinal trauma, regardless of approach used (39 vs 18%). The association of chronic donor site pain with residual back pain was also greater in the spinal reconstructive group. Thus, it appears that incidence of chronic donor site pain is more dependent on diagnosis than on surgical approach.

BACKGROUND: Relatively high plasma levels of soluble urokinase-type plasminogen activator receptor (suPAR) have been associated with focal segmental glomerulosclerosis and poor clinical outcomes in patients with various conditions. It is unknown whether elevated suPAR levels in patients with normal kidney function are associated with future decline in the estimated glomerular filtration rate (eGFR) and with incident chronic kidney disease. METHODS: We measured plasma suPAR levels in 3683 persons enrolled in the Emory Cardiovascular Biobank (mean age, 63 years; 65% men; median suPAR level, 3040 pg per milliliter) and determined renal function at enrollment and at subsequent visits in 2292 persons. The relationship between suPAR levels and the eGFR at baseline, the change in the eGFR over time, and the development of chronic kidney disease (eGFR <60 ml per minute per 1.73 m(2) of body-surface area) were analyzed with the use of linear mixed models and Cox regression after adjustment for demographic and clinical variables. RESULTS: A higher suPAR level at baseline was associated with a greater decline in the eGFR during follow-up; the annual change in the eGFR was -0.9 ml per minute per 1.73 m(2) among participants in the lowest quartile of suPAR levels as compared with -4.2 ml per minute per 1.73 m(2) among participants in the highest quartile (P<0.001). The 921 participants with a normal eGFR (≥ 90 ml per minute per 1.73 m(2)) at baseline had the largest suPAR-related decline in the eGFR. In 1335 participants with a baseline eGFR of at least 60 ml per minute per 1.73 m(2), the risk of progression to chronic kidney disease in the highest quartile of suPAR levels was 3.13 times as high (95% confidence interval, 2.11 to 4.65) as that in the lowest quartile. CONCLUSIONS: An elevated level of suPAR was independently associated with incident chronic kidney disease and an accelerated decline in the eGFR in the groups studied. (Funded by the Abraham J. and Phyllis Katz Foundation and others.).

OBJECTIVE: Anterior plate fixation has gained widespread acceptance for the treatment of cervical spondylosis, theoretically enhancing the rate of arthrodesis. There are few studies comparing fusion rates after anterior cervical discectomy and fusion (ACDF) with and without a plate. The purpose of this study was to evaluate the efficacy of anterior cervical plating for fusion enhancement after one- and two-level ACDF with cortical allograft. METHODS: A retrospective review was performed with 251 patients who underwent one- or two-level ACDF with cortical allograft and plate stabilization between 1993 and 1999. An independent surgeon reviewer determined fusion status and complications. A successful fusion was defined by the absence of lucency around the graft, evidence of bridging bone between the endplate and the graft, and the absence of movement on dynamic imaging scans. Follow-up data, ranging from 9 months to 3.6 years, were available for 233 patients. A control group of 289 patients who underwent ACDF without plating was described in a previously published report by the senior author (RWH). Therefore, a total of 540 patients were evaluated for determination of the efficacy of anterior cervical plating with cortical allograft bone. Statistical significance was determined by chi(2) test. RESULTS: The fusion rates for one- and two-level ACDF with anterior fixation were 96 and 91%, respectively, compared with 90 and 72% for one- and two-level ACDF without anterior fixation. The observed increases in fusion rates for both one- and two-level procedures proved to be statistically significant (P < 0.05). There were no recorded infectious, neurological, or graft-related complications among the cohort treated with anterior cervical plating. Compared with the results for the cohort treated without anterior cervical plates, there was a statistically significant decrease in the graft-related complication rate with the application of plates (P < 0.001). Two patients who received plates were noted to have adjacent-segment degenerative changes that required surgical intervention. No hardware fractures were noted; however, one patient was noted to have a single displaced screw, without clinical consequences. CONCLUSION: The use of anterior cervical plating after one- and two-level ACDF with allograft cortical bone significantly enhanced arthrodesis. The improved fusion rate and negligible complication rate associated with anterior cervical plating are compelling factors justifying its use in the treatment of cervical spondylosis.

OBJECTIVE: To determine rates and mechanisms of failure in 857 consecutive patients undergoing laparoscopic fundoplication for gastroesophageal reflux disease or paraesophageal hernia (1991-1998), and compare this population with 100 consecutive patients undergoing fundoplication revision (laparoscopic and open) at the authors' institution during the same period. SUMMARY BACKGROUND DATA: Gastroesophageal fundoplication performed through a laparotomy or thoracotomy has a failure rate of 9% to 30% and requires revision in most of the patients who have recurrent or new foregut symptoms. The frequency and patterns of failure of laparoscopic fundoplication have not been well studied. METHODS: All patients undergoing fundoplication revision were included in this study. Symptom severity was scored before and after surgery by patients on a 4-point scale. Evaluation of patients included esophagogastroscopy, barium swallow, esophageal motility, 24-hour ambulatory pH, and gastric emptying studies. Statistical analysis was performed with multiple chi-square analyses, Fisher exact test, and analysis of variance. RESULTS: Laparoscopic fundoplication was performed in 758 patients for gastroesophageal reflux disease and in 99 for paraesophageal hernia. Median follow-up was 2.5 years. Thirty-one patients (3.5%) have undergone revision for fundoplication failure. The mechanism of failure was transdiaphragmatic herniation of the fundoplication in 26 patients (84%). In 40 patients referred from other institutions, after laparoscopic fundoplication, only 10 (25%) had transdiaphragmatic migration (p < 0.01); a slipped or misplaced fundoplication occurred in 13 patients (32%), and a twisted fundoplication in 12 patients (30%). The failure mechanisms of open fundoplication (29 patients) followed patterns previously described. Fundoplication revision procedures were initiated laparoscopically in 65 patients, with six conversions (8%). The morbidity rate was 4% in laparoscopic procedures and 9% in open ones. There was one death, from aspiration and adult respiratory distress syndrome after open fundoplication. A year or more after revision operation, heartburn, chest pain, and dysphagia were rare or absent in 88%, 78%, and 91%, respectively, after laparoscopic revision, and were rare or absent in 91%, 83%, and 70%, respectively, after open revision, but 11 patients ultimately required additional operations for continued or recurrent symptoms, 3 after open revision (17%), and 8 after laparoscopic fundoplication (11%). CONCLUSIONS: Laparoscopic fundoplication failure is infrequent in experienced hands; the rate may be further reduced by extensive esophageal mobilization, secure diaphragmatic closure, esophageal lengthening (applied selectively), and avoidance of events leading to increased intraabdominal pressure. When revision is required, laparoscopic access may be used successfully by the laparoscopically experienced esophageal surgeon.

Abstract BACKGROUND The authors performed a comprehensive review of the efficacy of fluorodeoxyglucose positron emission tomography (FDG‐PET) in the detection of primary tumors in patients with cervical metastases from unknown primary tumors. METHODS Sixteen studies (involving a total of 302 patients) published between 1994 and 2003 were reviewed. These studies evaluated the role of FDG‐PET in the detection of unknown primary tumors after conventional workup. In all studies, conventional workup included either panendoscopy or computed tomographic/magnetic resonance imaging, and in 10 of 16 studies, both of these diagnostic techniques were performed before diagnosis. RESULTS The overall sensitivity, specificity, and accuracy rates of FDG‐PET in detecting unknown primary tumors were 88.3%, 74.9%, and 78.8%, respectively. Furthermore, FDG‐PET detected 24.5% of tumors that were not apparent after conventional workup. FDG‐PET imaging also led to the detection of previously unrecognized metastases in 27.1% of patients (regional, 15.9%; distant, 11.2%). FDG‐PET had notably low specificity and a high false‐positive rate (39.3%) in the tonsils. In contrast, the false‐positive rates for FDG‐PET of the base of tongue and hypopharynx were only 21.4% and 8.3%, respectively. FDG‐PET exhibited decreased sensitivity to tumors in the base of tongue (81.5%). The sensitivity of this technique at other sites was 90.5%. CONCLUSIONS FDG‐PET detected primary tumors that went undetected by other modalities in approximately 25% of cases and was sensitive in the detection of previously unrecognized regional or distant metastases in 27% of cases. FDG‐PET had low specificity for tonsillar tumors and low sensitivity for base‐of‐tongue malignancies. Cancer 2004. © 2004 American Cancer Society.

Although minimal model analysis of frequently sampled iv glucose tolerance tests (FSIGTs) to measure insulin sensitivity is well recognized, application has been limited by the need for endogenous insulin secretion. In the present study we determined whether use of exogenous insulin could permit minimal model assessment of insulin sensitivity (SI) to be extended to diabetic subjects. Normal volunteers had separate FSIGT assessments supplemented with both tolbutamide and insulin to accelerate glucose disappearance, while diabetics had a FSIGT supplemented only with insulin. There was a strong and highly significant correlation between the two assessments in normal subjects (r = 0.87; P less than 0.001), and the rank order of SI generally was maintained with the two assessments over a 3-fold range of SI; however, insulin-determined SI was 16% lower (3.4 +/- 0.4 vs. 4.1 +/- 0.4 x 10(-4) min/microU.microL; P less than 0.01). Diabetic subjects had markedly lower insulin sensitivity than controls (SI = 0.61 +/- 0.16; P less than 0.0001). Across all subjects, the level of fasting serum glucose was correlated inversely with both insulin sensitivity (r = -0.62; P less than 0.05) and acute insulin responses (r = -0.72; P less than 0.02); however, insulin sensitivity in diabetic subjects with little insulin secretion (0.6 +/- 0.2) was comparable to insulin sensitivity in diabetic subjects with near-normal responses (0.6 +/- 0.3). In subjects with fasting hyperglycemia, there were significant correlations between insulin sensitivity and body mass index, percent fat mass, and waist/hip ratio (all P less than 0.03). Among all female subjects, there was also a strong correlation between insulin sensitivity and upper body obesity, as measured by waist/hip ratio (r = -0.68; P less than 0.02). Model parameters also permitted glucose uptake to be estimated in diabetic vs. normal subjects at comparable hyperglycemia (11.1 mmol/L). Total glucose uptake was decreased in diabetic subjects (5.2 +/- 0.8 vs. 12.7 +/- 1.7 mg/min.kg in normals; P less than 0.001), insulin-dependent glucose uptake was diminished to a greater extent (1.3 +/- 0.4 vs. 6.2 +/- 1.2) than noninsulin-independent glucose uptake (3.9 +/- 0.5 vs. 6.4 +/- 0.9; both P less than 0.02). Administration of insulin permits minimal model FSIGT analysis to be applied to diabetic as well as normal subjects, yielding information about both insulin- and noninsulin-mediated glucose uptake as well as insulin sensitivity and insulin secretion.

BACKGROUND: Reactive oxygen species (ROS) are emerging as candidate mediators of growth and angiogenesis in cancer. Increased ROS often correlates with cell growth, e.g., Ras-transformed cells and cells treated with growth factors. While non-transformed cells respond to growth factors/cytokines with the regulated production of ROS, tumor cells in culture frequently overproduce H(2)O(2). We propose that NADPH oxidases (Nox) account for increased levels of ROS in some cancers. Previously, transfection of Nox1 into a prostate cancer cell line dramatically enhanced tumor growth (Arbiser et al.: PNAS 99:715-720, 2001). METHODS: Using immunohistochemistry, immunofluorescence, dihydroethidium staining, and Flow cytometry, we investigated the correlation between Nox1 and ROS in prostate cancer. RESULTS: Here, we demonstrate that human prostate tumors show increased H(2)O(2) levels. Furthermore, 80% of human prostate tumor samples show markedly increased Nox1 protein levels and increased mRNA levels. In addition, a series of cell lines developed from LNCaP prostate cancer cells that demonstrate increasing tumor and metastatic potential, show increased Nox1 and a parallel increase in H(2)O(2) levels. CONCLUSIONS: The results illustrate that human prostate cancer frequently show both increased H(2)O(2) and Nox1, and that in an animal model system increased Nox1/H(2)O(2) correlates with increased tumorigenicity.

Exposure therapy is a well-established treatment for Posttraumatic Stress Disorder (PTSD) that requires the patient to focus on and describe the details of a traumatic experience. Exposure methods include confrontation with frightening, yet realistically safe, stimuli that continues until anxiety is reduced. A review of the literature on exposure therapy indicates strong support from well-controlled studies applied across trauma populations. However, there are many misconceptions about exposure therapy that may interfere with its widespread use. These myths and clinical guidelines are addressed. It is concluded that exposure therapy is a safe and effective treatment for PTSD when applied as directed by experienced therapists.

Current pharyngeal deglutition theory has stressed the role of the pharyngeal constrictors as producing a peristaltic wave responsible for bolus propulsion through the pharynx. This thesis presents data obtained using manofluorography which supports the significance of tongue and laryngeal motion in swallowing. The usage of the term peristalsis to describe the constrictor contraction is challenged. The results of this quantitative study of swallowing in normal subjects, laryngectomized patients, and patients with restricted tongue motion show that tongue driving pressure and the negative pressure developed in the pharyngeal esophageal segment appear more important than the peristaltic-like pressure of the constrictors. Bolus transit is really dependent upon these two pressures. This model for analysis has clinical significance because it permits quantification of the pharyngeal swallowing mechanism.

PURPOSE: We compared hexaminolevulinate fluorescence cystoscopy with white light cystoscopy for detecting Ta and T1 papillary lesions in patients with bladder cancer. MATERIALS AND METHODS: A total of 311 patients with known or suspected bladder cancer underwent bladder instillation with 50 ml 8 mM HAL for 1 hour. The bladder was inspected using white light cystoscopy, followed by blue light (fluorescence) cystoscopy. Papillary lesions were mapped and resected for histological examination. RESULTS: Noninvasive pTa tumors were found in 108 of 196 evaluable patients (55.1%). In 31 patients (29%) at least 1 more tumor was detected by HAL than by white light cystoscopy (p<0.05). Six of these patients had no lesions detected by white light, 12 had 1 lesion detected by white light and more than 1 by HAL, and 13 had multiple Ta lesions detected by the 2 methods. Conversely at least 1 more tumor was detected by white light cystoscopy than by HAL cystoscopy in 10 patients (9%, 95% CI 5-16). Tumors invading the lamina propria (T1) were found in 20 patients (10.2%). At least 1 additional T1 tumor was detected by HAL but not by white light cystoscopy in 3 of these patients (15%), while at least 1 more T1 tumor was detected by white light cystoscopy than by HAL cystoscopy in 1 patient (5%, 95% CI 0-25). Detection rates for Ta tumors were 95% for HAL cystoscopy and 83% for white light cystoscopy (p=0.0001). Detection rates were 95% and 86%, respectively, for T1 tumors (p=0.3). HAL instillation was well tolerated with few local or systemic side effects. CONCLUSIONS: HAL fluorescence cystoscopy detected at least 1 more Ta and T1 papillary tumor than white light cystoscopy in approximately a third of the patients with such tumors. Whether this would translate to improved patient outcomes has yet to be determined.

BACKGROUND: Cardiovascular disease (CVD) fatality rates are higher for women than for men, yet obstructive coronary artery disease (CAD) is less prevalent in women. Coronary flow reserve (CFR), an integrated measure of large- and small-vessel CAD and myocardial ischemia, identifies patients at risk for CVD death, but is not routinely measured in clinical practice. We sought to investigate the impact of sex, CFR, and angiographic CAD severity on adverse cardiovascular events. METHODS: Consecutive patients (n=329, 43% women) referred for invasive coronary angiography after stress testing with myocardial perfusion positron emission tomography and with left ventricular ejection fraction >40% were followed (median, 3.0 years) for a composite end point of major adverse cardiovascular events, including cardiovascular death and hospitalization for nonfatal myocardial infarction or heart failure. The extent and severity of angiographic CAD were estimated by using the CAD prognostic index, and CFR was quantified by using positron emission tomography. RESULTS: Although women in comparison with men had lower pretest clinical scores, rates of prior myocardial infarction, and burden of angiographic CAD (P<0.001), they demonstrated greater risk of CVD events, even after adjustment for traditional risk factors, imaging findings, and early revascularization (adjusted hazard ratio, 2.05; 95% confidence interval, 1.05-4.02; P=0.03). Impaired CFR was similarly present among women and men, but in patients with low CFR (<1.6, n=163), women showed a higher frequency of nonobstructive CAD, whereas men showed a higher frequency of severely obstructive CAD (P=0.002). After also adjusting for CFR, the effect of sex on outcomes was no longer significant. When stratified by sex and CFR, only women with severely impaired CFR demonstrated significantly increased adjusted risk of CVD events (P<0.0001, P for interaction=0.04). CONCLUSIONS: Women referred for coronary angiography had a significantly lower burden of obstructive CAD in comparison with men but were not protected from CVD events. Excess cardiovascular risk in women was independently associated with impaired CFR, representing a hidden biological risk, and a phenotype less amenable to revascularization. Impaired CFR, particularly absent severely obstructive CAD, may represent a novel target for CVD risk reduction.

Cardiovascular diseases (CVDs) are the leading cause of mortality worldwide, reaching 31% of deaths in 2012 [1]. In particular, atherosclerosis and ischemic heart disease (IHD) are the main causes of premature death in Europe and are responsible for 42% of deaths in women and 38% in men under 75 years old [2]. The global economic impact of CVD is estimated to have been US $906 billion in 2015 and is expected to rise by 22% by 2030 [3]. Cardiovascular diseases also represent the major cause of disability in developed countries. It has been estimated that their growing burden could lead to a global increase in loss of disability-adjusted life years (DALYs), from a loss of 85 million DALYs in 1990 to a loss of ~150 million DALYs in 2020, becoming a major non-psychological cause of lost productivity [4]. Several risk factors contribute to the etiology and development of CVD; they are divided into those modifiable through lifestyle changes or by taking a pharmacologic treatment (e.g. for hypertension, smoking, diabetes mellitus, hypercholesterolemia) and those that are not modifiable (age, male gender, and family history) [5]. Elevated total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) blood concentrations are the major modifiable risk factors for coronary heart disease (CHD), whereas high concentrations of plasma high-density lipoprotein cholesterol (HDL-C) in certain conditions are considered protective [6]. Moreover, LDL-C remains a fundamental CV risk factor (and a main target of therapy) even when statins are largely used in the general population [7]. An examination of the data of 18 053 participants aged ≥ 20 years who participated in the National Health and Nutrition Examination Surveys (NHANES) from 1999 to 2006 showed that the unadjusted prevalence of hypercholesterolemia ranged from 53.2% to 56.1% in United States adults [8]. Differences related to gender and race or ethnicity were observed; in particular, a lower rate of control was found among women than men and lower rates of having a cholesterol check and being told about hypercholesterolemia were reported by African Americans and Mexican Americans than whites [8]. A recent report from the American Heart Association confirmed that in the US only 75.7% of children and 46.6% of adults present targeted TC levels (TC &lt; 170 mg/dl for children and &lt; 200 mg/dl for adults, in untreated individuals) [9]. The pattern is similar in other Western countries [10, 11].

Recent preclinical and clinical studies indicate that irradiation using ionizing radiation in the dose range of 15 to 30 Gy may reduce the occurrence of restenosis in patients who have undergone an angioplasty. Several delivery systems of intravascular brachytherapy have been developed to deliver radiation doses in this range with minimal normal tissue toxicity. In late 1995 the American Association of Physicists in Medicine (AAPM) formed a task group to investigate these issues and to report the current state of the art of intravascular brachytherapy physics. The report of this task group is presented here.

In recent years, there has been growing interest in the possible use of nutraceuticals to improve and optimize dyslipidemia control and therapy. Based on the data from available studies, nutraceuticals might help patients obtain theraputic lipid goals and reduce cardiovascular residual risk. Some nutraceuticals have essential lipid-lowering properties confirmed in studies; some might also have possible positive effects on nonlipid cardiovascular risk factors and have been shown to improve early markers of vascular health such as endothelial function and pulse wave velocity. However, the clinical evidence supporting the use of a single lipid-lowering nutraceutical or a combination of them is largely variable and, for many of the nutraceuticals, the evidence is very limited and, therefore, often debatable. The purpose of this position paper is to provide consensus-based recommendations for the optimal use of lipid-lowering nutraceuticals to manage dyslipidemia in patients who are still not on statin therapy, patients who are on statin or combination therapy but have not achieved lipid goals, and patients with statin intolerance. This statement is intended for physicians and other healthcare professionals engaged in the diagnosis and management of patients with lipid disorders, especially in the primary care setting.

CONTEXT: The past decade has brought many advances to the treatment of epilepsy, including many new pharmacological agents. Primary care physicians often care for patients with epilepsy and therefore should be familiar with the new options available. OBJECTIVE: To review data regarding the efficacy and tolerability of antiepileptic drugs introduced in the past decade. DATA SOURCES: A search of the Cochrane Central Register of Controlled Trials was performed to identify all published human and English-language randomized controlled trials evaluating the efficacy and tolerability of the antiepileptic drugs that have been approved for use in the United States since 1990. Additional reports evaluating pharmacokinetic properties were identified through a MEDLINE search as well as review of article bibliographies. STUDY SELECTION AND DATA EXTRACTION: Search terms included felbamate, gabapentin, lamotrigine, topiramate, tiagabine, levetiracetam, oxcarbazepine, and zonisamide. Studies were selected if efficacy and tolerability were reported as major outcome measures. Included studies (n = 55) enrolled a minimum of 20 adult subjects and had a treatment period of at least 6 weeks. DATA SYNTHESIS: Eight new antiepileptic drugs have been approved for use in the United States in the past decade. Each new antiepileptic drug is well tolerated and demonstrates statistically significant reductions in seizure frequency over baseline. No randomized controlled trials have compared the new antiepileptic drugs with each other or against the traditional antiepileptic drugs. Although there is no evidence to suggest that the newer medications are more efficacious, several studies have demonstrated broader spectrum of activity, fewer drug interactions, and overall better tolerability of the new agents. CONCLUSIONS: New antiepileptic drugs offer many options in the treatment of epilepsy, each with unique mechanisms of action as well as adverse effect profiles. The new antiepileptic drugs are well tolerated with few adverse effects, minimal drug interactions, and a broad spectrum of activity.