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Introduction: Accelerated cognitive decline is influenced by vascular aging. Arterial stiffness and pressure amplification, measures of vascular aging, are associated with lower cognitive performance though their association with cognitive domains has been understudied. Hypothesis: Arterial stiffness and pressure amplification are associated with lower global and domain-specific cognition among a sample of Caucasian and African American (AA) older adults. Methods: In a cross-sectional study of 4618 members from visit 5 (2011-2013) of ARIC (mean age: 75 years, 41% men, 20% AA), we measured arterial stiffness (carotid-femoral pulse wave velocity (cfPWV)) and pressure amplification (pulse pressure amplification (PPA), central pulse pressure (cPP) and carotid systolic blood pressure (cSBP)) using the Omron VP-1000 Plus device. Race-specific 25th percentile cut points were estimated for each measure. Domain-specific cognitive function was examined using the Delayed Word Recall Test (memory), Digit Symbol Substitution Test (executive function/processing speed), and Word Fluency Test (language). Test-specific z scores were calculated from sample means and standard deviations. A global cognition z score was generated by averaging the test-specific z scores. Linear regression was used to estimate the associations between race-specific 25th percentile dichotomies for arterial stiffness and pressure amplification measures with test-specific and global cognition z scores, adjusted for age, sex, education, ApoE4, heart rate, smoking and body mass index. Results: Among AAs, there was no significant association between measures of arterial stiffness and pressure amplification with either global or the domain-specific measures of cognition. Among Caucasians, all measures of arterial stiffness and pressure amplification were associated with lower global cognitive z scores (cfPWV: Beta (β) =-0.11, 95% Confidence Interval (CI): -0.19, -0.04; PPA: β=-0.11, 95% CI: -0.19, -0.03; cPP: β=-0.11, 95% CI: -0.18, -0.04; cSBP: β=-0.12, 95% CI: -0.20, -0.05). All measures of arterial stiffness and pressure amplification also were associated with lower executive function/processing speed (cfPWV: β=-0.09, 95% CI: -0.16, -0.03; PPA: β=-0.15, 95% CI: -0.22, -0.08; cPP: β=-0.14, 95% CI: -0.21, -0.07; cSBP: β=-0.13, 95% CI: -0.20, -0.07). High cfPWV was associated with lower memory (β=-0.12, 95% CI: -0.20, -0.04); and high cSBP was associated with lower language (β=-0.12, 95% CI: -0.20, -0.04). Conclusions: Arterial stiffness and measures of pressure amplification are inversely associated with global and domain-specific cognition in Caucasian older adults, but not in a smaller sample of AAs. Further study of the role of modifiable components of arterial aging on the preservation of cognition, particularly executive function/psychomotor speed, in older adulthood is warranted.

Background: As a high-flow, low-impedance organ, the brain is sensitive to excessive pressure and flow pulsatility. Increased pulsatility and arterial stiffness are hypothesized to contribute to cerebral microvascular damage linked to cognitive impairment. The association of arterial stiffness with mild cognitive impairment (MCI) and dementia in a biethnic population is not well characterized, and the association of pressure amplification with MCI and dementia is relatively unexplored. Objectives: To quantify the cross-sectional association of arterial stiffness, measured by aortic pulse wave velocity (PWV), and pressure amplification with MCI and dementia in a biethnic population of older adults. Methods: We included 4,945 adults (2,903 females; 1,069 African Americans; mean age 75 years) from the population-based ARIC-NCS. The Omron VP-1000 plus system was used to measure arterial stiffness (carotid-femoral PWV (cfPWV)) and pressure amplification measures (central systolic blood pressure (cSBP), central pulse pressure (cPP), and pulse pressure amplification (PPA)). A neurologist and neuropsychologist classified MCI and dementia using psychometric assessments, medical history, cerebral magnetic resonance imaging, and physical examinations, with adjudication by a third reviewer. We used multinomial logistic regression to evaluate associations of race-specific 25th percentile cut points of PWV and pressure amplification with normal cognition (reference), MCI and dementia. We stratified by race and adjusted for age, sex, and heart rate, ApoE4, education, smoking status, and study center. Results: There were 760 Caucasians with MCI and 110 with dementia, and 201 African Americans with MCI and 47 with dementia. Among Caucasians, those with lower PPA had a higher prevalence of dementia, odds ratio (OR)=1.84 (95% confidence interval (CI): 1.15, 2.97), comparing participants below the 25th percentile to those above it, and those with higher cSBP had a higher prevalence of MCI, OR=1.33 (95% CI: 1.09, 1.63), comparing participants above the 75th percentile to those below it. Also among Caucasians, those with higher cPP had a higher prevalence of MCI, OR=1.25 (95%CI: 1.01, 1.55), and dementia, OR=1.66 (95% CI: 1.00, 2.73), comparing participants above the 75th percentile to those below it. There were no statistically significant associations with cfPWV, among African Americans, and no evidence for effect modification by hypertension or diabetes. Conclusion: Arterial stiffness and components of pressure amplification were associated with MCI and dementia in Caucasians but not in African Americans, possibly due to the limited sample size. Longitudinal characterization of the observed associations is warranted to determine whether these measures are independent predictors of MCI and dementia among Caucasian and African American older adults.

Nutritional abnormalities are common in patients with gastroparesis (Gp), a disorder that may affect gastric motility and may delay emptying. The aim of this work was to identify relationships between serum nutrition markers including 25-OH vitamin D and gastric motility measures in Gp patients. We enrolled 59 consecutive gastric motility clinic patients (48 females, 11 males; mean age 44 years; 42 idiopathic; 17 diabetes mellitus) with Gp symptoms. The 25-OH vitamin D levels, for most patients slightly above the lower limit of normal (96.98 nmol/l ± 60.99), were lowest in diabetic range (DM) (75.68 nmol/l ± 34.22) vs. idiopathic (ID) (105.03 nmol/l ± 67.08) gastroparesis patients. First hour GET: one unit increase in 25-OH vitamin D level was associated 0.11 % improvement (95 % CI − 0.22, 0.01 p = 0.056) in gastric motility in all patients; this association, although marked in ID Gp patients, (− 0.13, CI − 0.25, − 0.01 p = 0.034), was not seen in DM Gp, (0.2, CI − 0.45, 0.87, p = 0.525). Fourth hour GET: Every unit increase of 25-OH vitamin D was associated with significant improvement in all patients, (0.11 % CI − 0.23, 0.01, p = 0.053), and some weak improvement in ID group, (0.11 % − 0.24, 0.01, p = 0.076) and absent in patients with DM (0.03, CI − 0.66, 0.72, p = 0.932). It is concluded that 25-OH vitamin D levels may influence gastric emptying. Underlying mechanisms for this observation might include the impact of 25-OH vitamin D on the health of the enteric nervous system. 25-OH vitamin D contributions to enteric nerve functions should be explored, particularly where autonomic nervous system comorbidities exist.

Rising health care costs are a major concern facing employers, managed care organizations, and other payers of health care services across the nation. Those who use the highest amount of health care resources are often those with multiple chronic conditions (Hoffman, Rice, and Sung 1996; Wolff, Starfield, and Anderson 2002), and a large portion of their costs are thought to be preventable through behavior modification and symptom management (Wolff, Starfield, and Anderson 2002). In an effort to contain costs for multimorbid populations, Population Health Management (PHM) programs have flourished in the past decade (Wheatley 2002; Juster et al. 2009). PHM has been described as “a proactive, organized, and cost-effective approach to prevention that utilizes newer technologies to help reduce morbidity while improving health status, health service use, and personal productivity of individuals in defined populations” (Chapman and Pelletier 2004). For managing those with chronic illness, interventions typically consist of nurse case management, telemonitoring, health coaching, motivational interviewing, and condition-specific health education to inform individuals about their condition and to assist them in developing self-management skills. The goals of PHM include improved health and productivity, reduction in modifiable risk factors, promotion of appropriate health care utilization, and reduction of preventable hospitalizations, which should ultimately result in lower health care costs (Johnson 2003; Kindig and Stoddart 2003; Villagra and Ahmed 2004; Seto 2008; Gary et al. 2009; Hibbard, Greene, and Tusler 2009). Despite the belief in the success of PHM programs, there is little evidence to suggest that they significantly reduce health care costs. The cost-effectiveness results in the literature tend to be inconclusive or mixed, with some studies demonstrating savings (Sidorov et al. 2002; Cousins and Liu 2003; Villagra and Ahmed 2004; Sylvia et al. 2008; Cloutier et al. 2009; Dall et al. 2010), whereas others do not (Galbreath et al. 2004; Turner et al. 2008; Nyman, Barleen, and Dowd 2009; Peikes et al. 2009). Results from these prior studies are often suspect, however, due to the frequent use of weak research designs. The validity issue is particularly concerning given that studies lacking in methodological rigor tend to report higher savings and return on investments (ROIs) than studies with more rigorous designs (Linden 2006; Maciejewski, Chen, and Au 2009). For example, studies that have demonstrated significant cost reductions are often those using weaker research methodologies such as pre-post designs without a comparison group, small sample sizes, inadequate observation lengths, and oversimplified statistical methods (Wagner 1998; Selby et al. 2003; Congressional Budget Office 2004; Fitzner et al. 2004). On the other hand, studies using randomized techniques often failed to detect significant cost savings related to PHM (Galbreath et al. 2004; Turner et al. 2008; Peikes et al. 2009). Even in experimental settings, however, the use of an intention-to-treat approach that does not consider intensity or duration of participation in the delivered intervention may dilute the impact of PHM programs and hinder the ability to detect significant cost savings. To confidently evaluate the fiscal impact of PHM programs, an improved method is needed. In health care settings, an experimental design is not often feasible due to ethical or contractual issues. The National Committee for Quality Assurance (NCQA) has recognized that randomized control trials are impractical within health plans (Fetterolf, Wennberg, and Devries 2004). Consequently, most researchers are limited to observational studies using some form of pre-post design (Wilson et al. 2004). The difficulty is that these types of designs are plagued by multiple confounding factors that need to be addressed to preserve the internal validity of the findings. One group of pre-post designs, although the most prominent design used for program evaluation (Johnson 2003; Linden, Adams, and Roberts 2003), can be limited by a number of confounders, including history, maturation, and regression to the mean. History effects may call into question the results if an event occurred between the pre and post measurements that impacted the outcome but was unrelated to the intervention or not of specific interest (Cook and Campbell 1979). Maturation involves the natural changes within participants through the passage of time, such as aging, tiredness, and hunger. This threat is of particular concern for PHM program evaluation given that a participant may improve naturally over time, regardless of whether they participate in the program (Cook and Campbell 1979). Regression to the mean suggests that extreme observations (in either direction) will eventually move toward the mean (Galton 1886), particularly if the observations are extreme due to measurement error (Cook and Campbell 1979). When PHM participants are selected based on extreme characteristics, such as a catastrophic event that leads to an expensive hospitalization, it is likely that participant costs will decrease over time regardless of the intervention (Cook and Campbell 1979; Fetterolf, Wennberg, and Devries 2004; Galton 1886). Using a one-group pre-post design, it is difficult to determine whether a change in participant outcomes is due to the intervention or to these confounding effects. The introduction of a comparison group can limit each of these threats. By measuring the changes in an equivalent comparison group from pre to post, which is also impacted by history, maturation, and regression to the mean, the remaining differences between groups can be more confidently attributed to PHM program involvement. Other common pre-post design elements that may limit study validity, even in a randomized setting, are the use of inadequate observation periods and few repeated measures to estimate the impact of PHM on cost. PHM evaluations frequently compare costs in the year prior to implementation to costs in the following year. Although this is an accepted method of evaluation, it may not adequately control for bias or other confounders. Employing a longitudinal design, with longer study periods and more frequent repeated cost measures, has been recommended as a better method for measuring changes over time in a natural environment (Linden, Adams, and Roberts 2003). Longitudinal data analysis can distinguish temporal changes within individuals from cross-sectional baseline group differences while accounting for the correlation between repeated observations. When the longitudinal relationship between PHM participation and cost is smaller than the cross-sectional relationship, the efficiency of the cost savings estimate can be improved by taking additional measurements on each person. Furthermore, increasing the within-subject variation in time with longer observation periods will increase the power, and thus the precision, of the savings estimate (Diggle et al. 2002). Longer follow-up periods can also help reduce any lingering effects of regression to the mean by continuing to measure group differences after the natural regression has occurred (Linden, Adams, and Roberts 2003). One method of analysis that combines the benefits of longitudinal data with a quasi-experimental design is mixed model smoothing. This semiparametric longitudinal modeling approach uses both fixed and random effects to estimate risk-adjusted cost trends over time while accounting for autocorrelation. The flexibility of mixed model smoothing allows for the detection of group-specific cost trend fluctuations over time, while the smoothing component reduces the influence of outliers (Anderson and Jones 1995; Wang 1998; Wand 2003; Ngo and Wand 2004; Maringwa et al. 2008; Jacqmin-Gadda, Proust-Lima, and Amieva 2010). In addition, inclusion of regular (e.g., quarterly) spline terms can aid in the measurement of natural changes due to seasonality and other history effects that impact both groups. Once these natural variations are removed, the remaining differences can be used to estimate the impact of PHM on costs. In a quasi-experimental setting, identification of an adequate comparison group is also key to ensuring the internal validity of savings estimates. Without randomization, it is important to reduce and/or statistically control for preexisting group differences as much as possible to assess causality. Selection bias is a common threat for quasi-experimental designs. When participants self-select their study group based on whether they choose to participate in PHM, selection bias is introduced. This is particularly concerning when those who choose to participate are inherently different from those who do not. Some of the methods for controlling selection bias include the use of a historical control group (Linden, Adams, and Roberts 2003; Dall et al. 2010), the selection of participations from other groups or sites that do not offer PHM services (Cousins and Liu 2003), and difference-in-difference models that use repeated observations to compare participants against themselves at earlier time points and then compare pre-post differences between groups (Nyman, Barleen, and Dowd 2009; Song et al. 2011). The primary goal of the current research is to develop a consistent model for producing sound PHM cost savings estimates in a quasi-experimental setting. The framework should generate savings estimates that can account for natural temporal change, selection bias, and subject-specific regression to the mean effects and should be flexible enough to accommodate regular updates for the continued monitoring of PHM program effectiveness. A secondary goal is to assess the influence of sampling variability on the precision of the savings estimate to perform basic tests of statistical inference.

Background and Purpose— Unrecognized or unreported stroke-like symptoms, called covert symptoms, occur in persons free of clinical stroke. Whether covert symptoms are associated with subclinical brain infarcts (SBIs) is unknown. This study examined the association between covert stroke-like symptoms and SBI/stroke in persons with no history of stroke or transient ischemic attack. Methods— A total of 1881 Atherosclerosis Risk in Communities (ARIC) participants free of clinical stroke or transient ischemic attack (40% male, 50% black, 47–70 years) were queried for covert symptoms and underwent cerebral MRI during the baseline MRI visit. Symptoms were reassessed after 3 years at Visit 4 (n=1001; 39% male, 50% black) and approximately 10 years with a follow-up MRI (n=1006; 40% male, 50% black, 61–83 years). Results— Covert symptoms were associated with prevalent SBI (OR, 1.94; 95% CI, 1.21–3.11; P =0.006). No support was found for associations between baseline MRI symptoms and SBI at the follow up MRI visit. In participants without SBI at baseline, symptoms at Visit 4 (OR, 2.96; 1.23–7.13; P =0.016) and symptoms at the follow-up MRI visit (OR, 4.29; 2.51–7.33; P P =0.014) on the follow-up MRI that were not seen on the baseline MRI. Conclusions— Covert neurological symptoms were associated with prevalent SBI, and when ascertained at the time of follow-up MRI, with new SBI. Covert symptoms may reflect heightened risk for infarcts.

Polymorphisms (SNP) in the glucocorticoid receptor (GR) gene can alter sensitivity to glucocorticoids. Previous studies of the N363S and BclI SNP in the GR gene have shown a metabolic syndrome phenotype in mostly non-African populations. The obesity phenotype of African Americans (AA) seems to be more severe than that of Caucasians.We aimed to assess the prevalence of N363S and BclI in obese and non-obese Caucasian (n=26) and African (n=23) Mississippians (age: 23-63 years) to investigate associations with body composition (body mass index/BMI, waist-to-hip ratio), metabolic parameters (salivary cortisol, fasting glucose and insulin, hemoglobin A1C, fructosamine, HOMA-IR index), and psychological stress perception (blood pressure/BP, perceived stress scale/PSS).All subjects were homozygous for wildtype N363N. BclI polymorphism genotype frequencies among the 23 AA were: homozygous CC (57%), GG (4%), and heterozygous CG (39%), and among the 26 white women: homozygous CC (35%), GG (19%), and heterozygous CG (46%). Linear and logistic regression analyses including a parsimonious model identified BMI as a statistically significant parameter between the two ethnic groups (BMI was 3.13 kg/m2 higher in AA). Within the AA group, BMI, waist-to-hip ratio, log (HOMA-IR), PSS scores, BP, and hyperlipidemia showed no statistically significant relationships for the BclI polymorphism. PSS scores were 15.2 for AA vs. 14.7 for white women (normal mean: 14.7 vs. 12.8).Black Mississippians have a higher BMI than whites, which may be related to the presence of the BclI polymorphism and increased glucocorticoid sensitivity. Although more blacks (52%) than whites (38%) had elevated BP, PSS scores in both groups suggest that a high BMI is not regarded as abnormal or stressful. This might negatively impact behavior change regarding lifestyle modifications with increased physical activity and healthier food choices. Larger studies, particularly in African populations, are needed to better define metabolic and psychological characteristics in relation to the N363S and BclI GR gene polymorphisms.

J Clin Hypertens (Greenwich). 2012;14:222–227. ©2012 Wiley Periodicals, Inc. The authors assessed the process of blood pressure (BP) measurement and level of adherence to recommended procedures at representative sites throughout a large academic health sciences center. A casual observer assessed the setting and observed the process, noting the equipment, technique, and BP recorded by site personnel. A trained observer then repeated the patient’s BP measurement following American Heart Association recommendations. Significant biases were observed between measurements by site personnel and the trained observer. Site personnel reported on average an increased systolic BP (SBP) of 5.66 mm Hg (95% confidence interval [CI], 3.09–8.23; P

Background African Americans have historically had high high-density lipoprotein cholesterol (HDL-C) compared with other races and ethnicities. Objective We sought to characterize whether there is a cross-sectional association between age and HDL-C in a contemporary community-based study of African Americans. Methods Cross-sectional data were modeled by logistic regression for predictors of HDL-C among African Americans, ages 35–74, participating in the baseline examination of a community-based study of cardiovascular disease in Jackson, Mississippi, during 2000–2004. After excluding persons taking lipid-lowering medications, hormone replacement therapy, oral contraceptives, or thyroid replacement, the analytical data set comprised 2420 persons (1370 women, 1050 men). Results HDL-C had a significant positive association with age after controlling for serum triglycerides, sex, waist circumference, percent dietary calories from carbohydrates, alcohol use, and leisure physical activity. Sex was a significant effect modifier of this relationship, whereby the increase in HDL-C with age was steeper for women than for men. Conclusions Cross-sectional analysis found a positive association of HDL-C with age while controlling for triglycerides. Careful evaluation of longitudinal data will be needed to confirm whether this is a true effect of aging, or a cohort or survivor effect.

Smaller infarcts (

The editorialists, who are all Annals statistical editors, discuss Wang and colleagues' findings and possible strategies to improve the conduct, reporting, and reproducibility of biomedical research.

There is little debate that realizing improvements in the quality of health care, especially for chronic conditions, will require changes in our physician payment practices. There remains substantial controversy, however, in how to structure a payment system to align resource allocation with quality of care (IOM Committee on Quality of Health Care in America 2001). Much attention has been devoted to pay-for-performance (P4P) programs that link some portion of physician or practice compensation to the attainment of specific quality of care objectives (Rosenthal et al. 2004, 2005; Rosenthal and Frank 2006). P4P programs continue to expand in number and scope even though research on the effects of P4P on quality has produced mixed results (Rosenthal et al. 2005; Rosenthal and Frank 2006; Rosenthal 2007; Rosof, Sirio, and Kmetik 2008; Greene and Nash 2009;). Health services leaders recommend P4P programs as part of the effort to address long-term health care spending growth (Antos et al. 2009). In addition to restructuring financial incentives, improvement in the care of chronic conditions frequently involves disease management of affected patients (Fireman, Bartlett, and Selby 2004; Wagner 2004; Wagner and Reid 2007;). Conventionally, disease management is provided by call center nurses who maintain telephonic contact with enrollees in order to assist them with the implementation of their chronic care regimens. While effort is made to have consistency between call center nurse and her patient panels, her contact with primary care providers is highly variable, and often not part of the disease management service mix. This lack of integration results in gaps in communication and coordination of care, both of which may have deleterious effects on the quality of care and patient outcomes. In recent years, a “second generation” of disease management has sought to integrate the remote, telephonic services, such as those typically provided by nurse care managers, within the primary care medical home (Villagra 2004; Casalino 2005; American Academy of Family Physicians 2008;). Co-locating the care management professional with the primary care clinicians may be a superior approach for improving care coordination, especially for patients with multimorbidity, which is the norm among elders (Boult et al. 2001; Boyd et al. 2005;). This article presents an evaluation of a chronic care improvement initiative that consisted of P4P practice-based care coordination augmented by third-party disease management with call center nurses dedicated to patients in intervention practices. The initiative (the “Intervention”) had three components: (1) a practice-based care coordination program using an on-site care coordinator (registered nurses [RNs], licensed practical nurses [LPNs], and medical assistants—a new position in the practices), (2) a P4P program in which practices were given a bonus payment for meeting specific quality indicator goals, and (3) a disease management program with call center nurses dedicated to patients in the intervention practices. The aims of this paper were to examine the effects of the intervention on quality of care measures and resource use for patients with diabetes mellitus, the most common chronic condition that is care managed by third-party firms and for which there is an evidence base supporting its responsiveness to care management (Villagra and Ahmed 2004; Von Korff et al. 2005; Mangione et al. 2006; Weber and Neeser 2006;). Moreover, diabetes is a condition that has behavioral change and care management potential in that it is relatively controllable by adherence to a medical regimen and lifestyle patterns that include healthy nutrition and activity (Hill-Briggs 2003). This evaluation was guided by the following, general research question: “What is the intervention effect on incentivized quality measures, and what is the broader effect of the intervention on the overall quality of care for patients with diabetes?” Specifically, we examined the effects of the intervention on (1) quality of care for the incentivized care indicators for diabetes, (2) quality of care for nonincentivized care indicators for diabetes, and (3) utilization and medical costs incurred by the patients with diabetes in the intervention practices. We hypothesized higher quality of medical care for enrollees with diabetes exposed to the intervention compared with others receiving usual primary care and conventional third-party disease management only. In examining the various nonincentivized measures, we sought to explore any positive halo effect of the intervention or any unintended consequences of the intervention such as decline in the nonincentivized quality of care measures (Casalino 1999; Forrest, Villagra, and Pope 2006;).

The purpose of this analysis was to characterize the natural history of weight change in the years prior to death among older persons and to examine how this pattern varies according to longevity and cause of death. Weight trajectories were analyzed by using data from 800 male decedents from the Baltimore Longitudinal Study of Aging (Maryland, 1958–2005) observed beginning an average of 19 years before death. A model including 3 distinct periods of weight change (weight stability/gain, mild weight loss, and accelerated weight loss before death) provided the best fit for all age-at-death groups. Approximately 9 years before death, the rate of weight loss increased to an average of 0.39 kg/year (P < 0.001) for all-cause mortality. For cancer deaths, weight loss accelerated significantly 3 years before death, regardless of age group. For cardiovascular deaths, the best-fitting inflection point increased with age, from 5 years for participants aged 60–69 years to 9–10 years before death for those aged 80 years or older. Results suggest that weight loss in older persons may begin earlier than previously believed. The duration of weight loss for noncancer deaths suggests that even distal changes in energy balance may be linked to risk of death.

The goals of this cross-sectional study were to explore correlates of walking speed in a large wide age-ranged population and to identify factors affecting lower walking speed at older ages. Participants were 3,872 community-dwelling adults in the first follow-up of the SardiNIA study who completed a 4-m walking test. Sex-specific correlates of walking speed included marital status, height, waist circumference, pulse wave velocity, comorbidity, subjective health, strength, and personality. Effect modifiers of the age–walking speed association included extraversion (

The long-term consequences of chronic manganese (Mn) exposure on neurological health is a topic of great concern to occupationally-exposed workers and in populations exposed to moderate levels of Mn. We have performed a comprehensive assessment of Mn effects on dopamine (DA) synapse markers using positron emission tomography (PET) in the non-human primate brain. Young male Cynomolgus macaques were given weekly i.v. injections of 3.3-5.0 mg Mn/kg (n = 4), 5.0-6.7 mg Mn/kg (n = 5), or 8.3-10.0 mg Mn/kg (n = 3) for 7-59 weeks and received PET studies of various DA synapse markers before (baseline) and at one or two time points during the course of Mn exposure. We report that amphetamine-induced DA release measured by PET is markedly impaired in the striatum of Mn-exposed animals. The effect of Mn on DA release was present in the absence of changes in markers of dopamine terminal integrity determined in post-mortem brain tissue from the same animals. These findings provide compelling evidence that the effects of Mn on DA synapses in the striatum are mediated by inhibition of DA neurotransmission and are responsible for the motor deficits documented in these animals.

Background Cigarette smoking is a risk factor for stroke, but the mechanisms by which smoking contributes to stroke are not well understood. This study aimed to evaluate the roles of lung function (represented by forced expiratory volume in the first second (FEV 1 )) and aldosterone as potential mediators of the association of smoking with stroke. Methods and Results The data were derived from 5010 Jackson Heart Study participants who had mean follow‐up of 97.9 months. Using the Cox proportional hazards model, we estimated the hazard ratios of smoking for total stroke with and without adjustment for FEV 1 and/or aldosterone at baseline after controlling for the confounders. The hazard ratio for current smoking (versus never smoking) was 2.70 (95% CI 1.71 to 4.25) for total stroke after adjustment for the confounders. Additional adjustment for FEV 1 and aldosterone reduced the hazard ratio to 2.32 (95% CI 1.42 to 3.79), suggesting that 22.4% of the excess risk of current smoking for total stroke is mediated by these factors. FEV 1 and aldosterone account for 13.1% and 12.1%, respectively, of the excess risk. The hazard ratio for FEV 1 increased (0.61 versus 0.65) after including systemic inflammatory marker C‐reactive protein, and the hazard ratios for aldosterone were comparable for the models that included all confounders and smoking status with or without different blood pressure measurements. Conclusions Our findings suggest that the difference in stroke risk between current and never smokers may develop partially through pathways involving lung function and aldosterone and that the mediation effect through aldosterone is independent of blood pressure.

Item does not contain fulltext BACKGROUND AND AIMS: EUS-guided FNA or biopsy sampling is widely practiced. Optimal sonographic visualization of the needle is critical for image-guided interventions. Of the several commercially available needles, bench-top testing and direct comparison of these needles have not been done to reveal their inherent echogenicity. The aims are to provide bench-top data that can be used to guide clinical applications and to promote future device research and development. METHODS: Descriptive bench-top testing and comparison of 8 commonly used EUS-FNA needles (all size 22 gauge): SonoTip Pro Control (Medi-Globe); Expect Slimline (Boston Scientific); EchoTip, EchoTip Ultra, EchoTip ProCore High Definition (Cook Medical); ClearView (Conmed); EZ Shot 2 (Olympus); and BNX (Beacon Endoscopic), and 2 new prototype needles, SonoCoat (Medi-Globe), coated by echogenic polymers made by Encapson. Blinded evaluation of standardized and unedited videos by 43 EUS endoscopists and 17 radiologists specialized in GI US examination who were unfamiliar with EUS needle devices. RESULTS: There was no significant difference in the ratings and rankings of these needles between endosonographers and radiologists. Overall, 1 prototype needle was rated as the best, ranking 10% to 40% higher than all other needles (P < .01). Among the commercially available needles, the EchoTip Ultra needle and the ClearView needle were top choices. The EZ Shot 2 needle was ranked statistically lower than other needles (30%-75% worse, P < .001). CONCLUSIONS: All FNA needles have their inherent and different echogenicities, and these differences are similarly recognized by EUS endoscopists and radiologists. Needles with polymeric coating from the entire shaft to the needle tip may offer better echogenicity.

Introduction The impact of blood pressure on brain volumes may be time-dependent or pattern-dependent. Methods Of 1678 participants from the Atherosclerosis Risk in Communities Neurocognitive Study, we quantified the association between measures and patterns of blood pressure over three time points (∼24 or ∼15 years prior and concurrent with neuroimaging) with late life brain volumes. Results Higher diastolic blood pressure ∼24 years prior, higher systolic and pulse pressure ∼15 years prior, and consistently elevated or rising systolic blood pressure from ∼15 years prior to concurrent with neuroimaging, but not blood pressures measured concurrent with neuroimaging, were associated with smaller volumes. The pattern of hypertension ∼15 years prior and hypotension concurrent with neuroimaging was associated with smaller volumes in regions preferentially affected by Alzheimer's disease (e.g., hippocampus: −0.27 standard units, 95% CI: −0.51, −0.03). Discussion Hypertension 15 to 24 years prior is relevant to current brain volumes. Hypertension followed by hypotension appears particularly detrimental.

Background To determine whether prediabetes and diabetes in older adults are associated with arterial stiffness measured in central and peripheral arteries and to examine characteristics that modify these associations. Methods Cohort members attending the 5th exam (2011-2013) of the Atherosclerosis Risk in Communities (ARIC) study had pulse wave velocity (PWV) measures performed at the carotid-femoral (cfPWV), brachial-ankle (baPWV), and femoral-ankle (faPWV) segments. Fasting glucose ≥126mg/dl, glycated hemoglobin (HbA1c) ≥6.5%, or currently taking diabetes medication defined diabetes. Fasting glucose 100-125mg/dl or HbA1c 5.7%-6.4% among those without diabetes defined prediabetes. Cross-sectional associations were modeled using multivariable linear regression. Results Among 4,279 eligible participants with cfPWV measures (mean age 75 years), 22% were African-American, 25.5% had diabetes, and 54.7% had prediabetes. Compared to those with normal glucose, cfPWV was 95.8cm/s higher (stiffer) on average for those with diabetes (for reference: being 1 year older was associated with 14.4cm/s higher cfPWV). Similar findings were seen for diabetes and baPWV, although attenuated. Interestingly, faPWV was 17.6cm/s lower for those with diabetes compared to normal glucose. There was a significant positive association between baPWV and prediabetes. Among those with diabetes, cfPWV was higher for those with albuminuria, reduced kidney function, duration of diabetes ≥10 years, and elevated HbA1c (HbA1c ≥7). Conclusion Among older adults, diabetes is associated with higher central arterial stiffness and lower peripheral arterial stiffness, and prediabetes is associated with higher baPWV. Cross-sectionally, the magnitude of the effect of diabetes on central stiffness is equivalent to 6 years of arterial aging.

We prospectively examined vBMD and structural bone parameters assessed by QCT among participants of the InCHIANTI study over a 6-yr follow-up. Periosteal apposition occurred both in men and women. Endocortical resorption causes bone loss in older women despite periosteal apposition. Introduction: To address the hypothesis that age-related changes in BMD and bone geometry may be different in men and women, we prospectively examined volumetric BMD (vBMD) and structural bone parameters assessed by QCT among participants of the InCHIANTI study over a 6-yr follow-up. Materials and Methods: Three hundred forty-five men and 464 women 21–102 yr of age from the InCHIANTI study, a population-based study in Tuscany, Italy, were included. Tibial QCT bone parameters were measured at enrollment (1998–2000) and at 3- (2001–2003) and 6-yr (2004–2006) follow-ups. Results: Periosteal apposition occurred both in men and women. The annual rate of bone periosteal apposition was higher in younger than in older men, whereas in women, the rate of apposition was homogenous across age groups. The age-related medullary expansion, expression of endocortical resorption, was significantly higher in women compared with men. In women, but not in men, accelerated endocortical resorption not sufficiently balanced by periosteal apposition caused accelerated loss in cortical bone mass. The cross-sectional moment of inertia decreased progressively over the life span in both sexes. Conclusions: Endocortical resorption causes bone loss in older women despite periosteal apposition. Obtaining a balance between endocortical resorption and periosteal apposition should be the target for interventions aimed to decrease bone loss and prevent osteoporosis in older women.

Background: When using observational data to compare the effectiveness of medications, it is essential to account parsimoniously for patients' longitudinal characteristics that lead to changes in treatments over time. Objectives: We developed a method of estimating effects of longitudinal treatments that uses subclassification on a longitudinal propensity score to compare outcomes between a new drug (exenatide) and established drugs (insulin and oral medications) assuming knowledge of the variables influencing the treatment assignment. Research Design/Subjects: We assembled a retrospective cohort of patients with diabetes mellitus from among a population of employed persons and their dependents. Methods: The data, from i3Innovus, includes claims for utilization of medications and inpatient and outpatient services. We estimated a model for the longitudinal propensity score process of receiving a medication of interest. We used our methods to estimate the effect of the new versus established drugs on total health care charges and hospitalization. Results: We had data from 131,714 patients with diabetes filling prescriptions from June through December 2005. Within propensity score quintiles, the explanatory covariates were well-balanced. We estimated that the total health care charges per month that would have occurred if all patients had been continually on exenatide compared with if the same patients had been on insulin were minimally higher, with a mean monthly difference of $397 [95% confidence interval (CI), $218-$1054]. The odds of hospitalization were also comparable (relative odds, 1.02; 95% CI, 0.33-1.98). Conclusions: We used subclassification of a longitudinal propensity score for reducing the multidimensionality of observational data, including treatments changing over time. In our example, evaluating a new diabetes drug, there were no demonstrable differences in outcomes relative to existing therapies.

The way a construct is measured can differ across cohort study visits, complicating longitudinal comparisons. We demonstrated the use of factor analysis to link differing cognitive test batteries over visits to common metrics representing general cognitive performance, memory, executive functioning, and language.We used data from three visits (over 26 years) of the Atherosclerosis Risk in Communities Neurocognitive Study (N = 14,252). We allowed individual tests to contribute information differentially by race, an important factor to consider in cognitive aging. Using generalized estimating equations, we compared associations of diabetes with cognitive change using general and domain-specific factor scores versus averages of equally weighted standardized test scores.Factor scores provided stronger associations with diabetes at the expense of greater variability around estimates (e.g., for general cognitive performance, -0.064 standard deviation units/year, standard error = 0.015, vs. -0.041 standard deviation units/year, standard error = 0.014), which is consistent with the notion that factor scores more explicitly address error in measuring assessed traits than averages of standardized tests.Factor analysis facilitates use of all available data when measures change over time, and further, it allows objective evaluation and correction for differential item functioning.

We recently showed that Alzheimer's disease patients have lower plasma concentrations of the phosphatidylcholines (PC16:0/20:5; PC16:0/22:6; and PC18:0/22:6) relative to healthy controls. We now extend these findings by examining associations between plasma concentrations of these PCs with cognition and brain function (measured by regional resting state cerebral blood flow; rCBF) in non-demented older individuals. Within the Baltimore Longitudinal Study of Aging neuroimaging substudy, participants underwent cognitive assessments and brain 15O-water positron emission tomography. Plasma phosphatidylcholines concentrations (PC16:0/20:5, PC16:0/22:6, and PC18:0/22:6), cognition (California Verbal Learning Test (CVLT), Trail Making Test A&B, the Mini-Mental State Examination, Benton Visual Retention, Card Rotation, and Fluencies—Category and Letter), and rCBF were assessed. Lower plasma phosphatidylcholine concentrations were associated with lower baseline memory performance (CVLT long delay recall task—PC16:0/20:5: −2.17–1.39−0.60 p = 0.001 (β with 95% confidence interval subscripts)) and lower rCBF in several brain regions including those associated with memory performance and higher order cognitive processes. Our findings suggest that lower plasma concentrations of PC16:0/20:5, PC16:0/22:6, and PC18:0/22:6 are associated with poorer memory performance as well as widespread decreases in brain function during aging. Dysregulation of peripheral phosphatidylcholine metabolism may therefore be a common feature of both Alzheimer's disease and age-associated differences in cognition.

BACKGROUND Although cerebral lesions 3 mm or larger on imaging are associated with incident stroke, lesions smaller than 3 mm are typically ignored. OBJECTIVE To examine stroke risks associated with subclinical brain lesions (

Background Few studies have examined the impact of lifecourse socioeconomic position ( SEP ) on cardiovascular disease ( CVD ) risk among African Americans. Methods and Results We used data from the Jackson Heart Study ( JHS ) to examine the associations of multiple measures of lifecourse SEP with CVD events in a large cohort of African Americans. During a median of 7.2‐year follow‐up, 362 new or recurrent CVD events occurred in a sample of 5301 participants aged 21 to 94. Childhood SEP was assessed by using mother's education, parental home ownership, and childhood amenities. Adult SEP was assessed by using education, income, wealth, and public assistance. Adult SEP was more consistently associated with CVD risk in women than in men: age‐adjusted hazard ratios for low versus high income (95% CIs), 2.46 (1.19 to 5.09) in women and 1.50 (0.87 to 2.58) in men, P for interaction=0.1244, and hazard ratio for low versus high wealth, 2.14 (1.39 to 3.29) in women and 1.06 (0.62 to 1.81) in men, P for interaction=0.0224. After simultaneous adjustment for all adult SEP measures, wealth remained a significant predictor of CVD events in women ( HR =1.73 [1.04, 2.85] for low versus high). Education and public assistance were less consistently associated with CVD . Adult SEP was a stronger predictor of CVD events in younger than in older participants ( HR for high versus low summary adult SEP score 3.28 [1.43, 7.53] for participants ≤50 years, and 1.90 (1.36 to 2.66) for participants >50 years, P for interaction 0.0846). Childhood SEP was not associated with CVD risk in women or men. Conclusions Adult SEP is an important predictor of CVD events in African American women and in younger African Americans. Childhood SEP was not associated with CVD events in this population.

The objective of our study was to evaluate outcomes and complications related to the management of Bosniak category IIF, III, and IV renal cysts.For this multiinstitutional retrospective study, a Web-based Research Electronic Data Capture (REDCap) data registry was used to record data of 286 adult patients with 312 prospectively classified Bosniak IIF, III, and IV renal cysts diagnosed between January 2000 and October 2011. Included patients were managed by surgery (n = 86), percutaneous ablation (n = 19), or imaging surveillance of 1 year or more (n = 181). The median number of years of clinical surveillance was 2.4 years (range, 0-11.7 years), 2.6 years (range, 0.4-11.4 years), and 3.2 years (range, 1.1-11.6 years) for patients managed by surgery, ablation, and imaging surveillance, respectively. Pathologic and survival outcomes and complications related to management were evaluated.The malignancy rate at surgical pathology was 38% (3/8) for Bosniak IIF, 40% (29/72) for Bosniak III, and 90% (18/20) for Bosniak IV renal cysts. There were no metastases or deaths (0/144) directly related to Bosniak IIF renal cysts. There were no deaths (0/113) directly related to Bosniak III renal cysts, although one patient (1/113) developed local progression and lung metastases after thermal ablation. One patient with a Bosniak IV renal cyst (1/29) presented with and died of metastatic disease. Moderate to severe complications occurred in 19% (16/86), 5% (1/19), and 0% (0/181) of patients managed by surgery, ablation, and imaging surveillance, respectively (p0.0001). Severe complications occurred in 7% (6/86) of surgical patients and included multiorgan failure (n = 2), acute myocardial infarction (n = 1), acute ischemic stroke (n = 1), conversion to hemodialysis-dependent chronic kidney disease (n = 1), and postoperative severe hemorrhage (n = 1).There were no deaths from Bosniak IIF or III renal cysts regardless of management approach. Moderate to severe complications are frequent in patients managed by surgery.

Background The calibration to isotope dilution mass spectrometry-traceable creatinine is essential for valid use of the new Chronic Kidney Disease Epidemiology Collaboration equation to estimate the glomerular filtration rate. Methods For 5,210 participants in the Jackson Heart study (JHs), serum creatinine was measured with a multipoint enzymatic spectrophotometric assay at the baseline visit (2000–2004) and remeasured using the Roche enzymatic method, traceable to isotope dilution mass spectrometry in a subset of 206 subjects. The 200 eligible samples (6 were excluded, 1 for failure of the remeasurement and 5 for outliers) were divided into 3 disjoint sets—training, validation and test—to select a calibration model, estimate true errors and assess performance of the final calibration equation. The calibration equation was applied to serum creatinine measurements of 5,210 participants to estimate glomerular filtration rate and the prevalence of chronic kidney disease (CKD). Results The selected Deming regression model provided a slope of 0.968 (95% confidence interval [CI], 0.904–1.053) and intercept of −0.0248 (95% CI, −0.0862 to 0.0366) with R 2 value of 0.9527. Calibrated serum creatinine showed high agreement with actual measurements when applying to the unused test set (concordance correlation coefficient 0.934, 95% CI, 0.894–0.960). The baseline prevalence of CKD in the JHS (2000–2004) was 6.30% using calibrated values compared with 8.29% using noncalibrated serum creatinine with the Chronic Kidney Disease Epidemiology Collaboration equation ( P Conclusions A Deming regression model was chosen to optimally calibrate baseline serum creatinine measurements in the JHS, and the calibrated values provide a lower CKD prevalence estimate.

Introduction: Functional impairments influence the performance of activities of daily living and may result in dependence on others for basic self-care needs. Lower individual-level socioeconomic status (SES) is associated with more self-reported disability and lower measured walking speeds which convey a higher risk of cardiovascular and all-cause mortality. The role of neighborhood-level SES on these functional outcomes has not been widely examined. Hypothesis: We hypothesized that residing in a socioeconomically disadvantaged neighborhood is inversely associated with physical function, after accounting for individual-level SES. Methods: We included 5,388 participants (42% male, 19% black, mean age: 76 years) from the 2011-2013 examination of the ARIC cohort. Neighborhood SES was constructed from census-tract data and an index score was derived based on aggregate z-score estimates from the following 6 dimensions: median household income; median value of owner-occupied units; % adults with a high school degree; % adults with a college degree; % households receiving interest, dividend or rental income; and % adults employed in executive, managerial or professional occupations. Race-specific tertiles were generated to indicate low, middle and high neighborhood SES. The Short Physical Performance Battery (SPPB) was used to derive a summary score (0-12) of physical function based on the individual’s performance on gait speed, chair stands and balance exercises. Negative binomial regression was used to quantify the difference in the log of expected counts in the SPPB score between race-stratified low, middle and high neighborhood SES, adjusting for age, sex, body mass index (BMI), smoking, hypertension, diabetes, study center, and education as a measure of individual-level SES. The multivariable-adjusted effect of neighborhood SES on a 4-meter walking speed test and on grip strength was estimated by least-squares regression. Results: Blacks had a slower walking speed, higher grip strength and lower SPPB score compared to whites. Hypertension, higher BMI, and lower education were more prevalent among white and black individuals from low SES neighborhoods, compared to those from high SES neighborhoods. White participants residing in a low SES neighborhood had a 1.1 kilogram (95% CI: 0.3, 1.9) greater grip strength compared to those residing in high SES neighborhoods. Neighborhood SES was not associated with walking speed and SPPB in either whites or blacks. Associations were robust to adjustment for education. Conclusions: Individual but not neighborhood-level SES was associated with poorer physical function. The prevalence of adverse clinical comorbidities was higher among both black and white participants living in disadvantaged neighborhoods. Poorer individual, modifiable health and SES measures may be targets for interventions to reduce functional disparities.

Background Genetic heritability and expression study have shown that different diabetes traits have common genetic components and pathways. A computationally efficient pathway analysis of GWAS results will benefit post-GWAS study of SNP associations and identification of common genetic pathways from diabetes GWAS can help to improve understanding of the disease pathogenesis. Results We proposed a uniform-score gene-set analysis (USGSA) with implemented package to unify different gene measures by a uniform score for identifying pathways from GWAS data, and use a pre-generated permutation distribution table to quickly obtain multiple-testing adjusted p-value. Simulation studies of uniform score for four gene measures (minP, 2ndP, simP and fishP) have shown that USGSA has strictly controlled family-wise error rate. The power depends on types of gene measure. USGSA with a two-stage study strategy was applied to identify common pathways associated with diabetes traits based on public dbGaP GWAS results. The study identified 7 gene sets that contain binding motifs at promoter region of component genes for 5 transcription factors (TFs) of FOXO4, TCF3, NFAT, VSX1 and POU2F1, and 1 microRNA of mir-218. These gene sets include 25 common genes that are among top 5% of the gene associations over genome for all GWAS. Previous evidences showed that nearly all of these genes are mainly expressed in the brain. Conclusions USGSA is a computationally efficient approach for pathway analysis of GWAS data with promoted interpretability and comparability. The pathway analysis suggested that different diabetes traits share common pathways and component genes are potentially regulated by common TFs and microRNA. The result also indicated that the central nervous system has a critical role in diabetes pathogenesis. The findings will be important in formulating novel hypotheses for guiding follow-up studies. Electronic supplementary material The online version of this article (doi:10.1186/s12864-015-1515-3) contains supplementary material, which is available to authorized users.

Probit-normal models have attractive properties compared to logit-normal models. In particular, they allow for easy specification of marginal links of interest while permitting a conditional random effects structure. Moreover, programming fitting algorithms for probit-normal models can be trivial with the use of well-developed algorithms for approximating multivariate normal quantiles. In typical settings, data cannot distinguish between probit and logit conditional link functions. Therefore, if marginal interpretations are desired, the default conditional link should be the most convenient one. We refer to models with a probit conditional link, an arbitrary marginal link, and a normal random effect distribution as link-probit-normal models. In this article we outline these models and discuss appropriate situations for using multivariate normal approximations for estimation. Unlike other articles in this area that focus on very general situations and implement Markov chain or MCEM algorithms, we focus on ...

OBJECTIVES: To assess relationships between vision (contrast sensitivity, stereopsis, visual acuity) and a performance-based measure of ability to implement new medications.DESIGN: Cross-sectional analysis; prospective cohort study.SETTING: Community-based.PARTICIPANTS: Three hundred thirty-five participants aged 73 to 82 in Year 3 of the Women's Health and Aging Study 11, a representative sample of the two-thirds least-disabled community-dwelling women.MEASUREMENTS: Hopkins Medication Schedule Pillbox Ratio, a joint measure of accuracy and time, and a performance-based measure of ability to Implement a prescription. Participants received written and verbal instructions for taking two medications and were directed to place pills in a pillbox accordingly. Vision assessments: contrast sensitivity (Pelli-Robson letter sensitivity chart), stereopsis (Randot Circles), and visual acuity (Early Treatment Diabetic Retinopathy Study eye chart).RESULTS: Forty-four percent (148/335) of women incorrectly placed one or both medications. Each vision measure was positively associated with Pillbox Ratio scores and varied with cognition and time to completion. Better visual acuity, contrast sensitivity, and stereopsis were each associated with better performance in women with poor cognition who filled the pillbox quickly. Additionally, better visual acuity was associated with better performance in participants with good cognition who filled the pillbox slowly; better stereopsis was associated with better performance in participants with poor cognition who filled the pillbox slowly and whose stereoacuity was below normal.CONCLUSION: Visual acuity, contrast sensitivity, and stereopsis should be considered potential risk factors for impaired ability to implement a medication regimen in older adults. Future research should investigate the role of vision, including contrast sensitivity and stereopsis, on performance of other instrumental activities of daily living.

Objectives: To determine the agreement between self-report of chronic disease and validated evidence of disease using multiple ascertainment methods and to assess effects of cognition, education, age, and comorbidity. Design: Cross-sectional analysis. Setting: Community Baltimore, Maryland. Participants: One thousand two community-dwelling disabled women aged 65 and older. Measurements: Kappa statistics were calculated to determine the relationship between self-report of 14 diseases and standardized algorithms. Analyses were stratified using Mini-Mental State Examination score, education, number of chronic diseases, and age. Results: Kappa was excellent for hip fracture (HF), Parkinson's disease (PD), diabetes mellitus (DM), cancer, stroke, and disc disease (DD); fair to good for angina pectoris, congestive heart failure, and myocardial infarction; and poor for peripheral arterial disease, spinal stenosis, osteoporosis, arthritis, and lung disease. Overall, kappa decreased with decreasing cognition and education, increasing age, and four or more diseases. Conclusion: In disabled older women, self-report of physician diagnosis of HF, PD, DM, cancer, stroke, and DD appears valid. In general, increasing comorbidity and age and decreasing cognition and education do not reduce validity for diseases where agreement was excellent overall.

Objective: To determine the predictors and incidence of hypothermia in patients undergoing head and neck surgery. Study Design: Retrospective analysis. Methods: Patients were either not warmed (n = 43) or actively warmed with forced-air warming (n = 25). Clinical variables that were assessed as predictors of core body temperature included age, body mass, duration of procedure, estimated blood loss, amount of intravenous fluids administered, and the use of forced-air warming. The incidence of severe intraoperative hypothermia and potential hypothermia-related complications was also examined. Results: The study demonstrated that advanced age is a risk factor for hypothermia and decreased body mass is associated with lower final body temperatures in the groups of patients that was not warmed. After adjusting for differences in the ages and weights between the two groups, the mean core body temperature was found to be 0.4°C lower in the patients who were not warmed. Severe intraoperative hypothermia occurred in 5 of 38 patients (11.6%) who were not warmed and 2 of 23 patients (8.0%) who were warmed. The complications associated with hypothermia included delayed time to extubation, the development of neck seromas, and flap dehiscence. Conclusions: Patients undergoing head and neck surgery are at risk for the development of intraoperative hypothermia and require careful temperature monitoring. Elderly patients and patients with low body mass are more prone to develop low intraoperative core body temperatures. Active warming with forced-air warmers should be considered for patients at risk for intraoperative hypothermia and for patients who develop hypothermia intraoperatively, to avoid hypothermiarelated complications.

We estimate the fraction of disease cases, and the fraction of their total medical expenditures, attributable to smoking for two disease groups: (LC) lung and laryngeal cancer and chronic obstructive pulmonary disease, (CHD) cardiovascular disease, stroke and other smoking-caused cancers. We use a generalized additive model to predict the probability of disease; and a semi-parametric, two-part cost model to estimate the average difference in medical expenditures for persons with and without disease. We estimate that 53% and 13% of the medical expenditures for persons with LC or CHD are attributable to smoking.

Background and Purpose— The relationships between cerebrovascular lesions visible on imaging and cognition are complex. We explored the possibility that the cerebral cortical volume mediated these relationships. Methods— Total of 1906 nondemented participants (59% women; 25% African–American; mean age, 76.6 years) in the Atherosclerosis Risk in Communities (ARIC) study underwent cognitive assessments, risk factor assessments, and quantitative MRI for white matter hyperintensities (WMH) and infarcts. The Freesurfer imaging analysis pipeline was used to determine regional cerebral volumes. We examined the associations of cognitive domain outcomes with cerebral volumes (hippocampus and separate groups of posterior and frontal cortical regions of interest) and cerebrovascular imaging features (presence of large or small cortical/subcortical infarcts and WMH volume). We performed mediation pathway analyses to assess the hypothesis that hippocampal and cortical volumes mediated the associations between cerebrovascular imaging features and cognition. Results— In unmediated analyses, WMH and infarcts were both associated with worse psychomotor speed/executive function. In mediation analyses, WMH and infarct associations on psychomotor speed/executive function were significantly attenuated, but not abolished, by the inclusion of the posterior cortical regions of interest volume in the models, and the infarcts on psychomotor speed/executive function association were attenuated, but not abolished, by inclusion of the frontal cortical regions of interest volume. Conclusions— Both WMH and infarcts were associated with cortical volume, and both lesions were also associated with cognitive performance, implying shared pathophysiological mechanisms. Although cross-sectional, our findings suggest that WMH and infarcts could be proxies for clinically covert processes that directly damage cortical regions. Microinfarcts are 1 candidate for such a clinically covert process.

Study Objectives: To determine the short-term variability of indices of disturbed respiration and sleep during 2 nights of unattended nonlaboratory polysomnography conducted several months apart. Design: Participants were randomly selected using a block design with stratification on preliminary estimates of 2 criteria: respiratory disturbance index [RDI 3% (apnea or hypopnea events associated with > 3% O 2 desaturation): 85%). The RDI and sleep data from initial and repeated polysomnography were compared. Setting: NA Participants: A subset of 99 participants in the Sleep Heart Health Study who agreed to have a repeat polysomnogram within 4 months of their original study. Interventions: NA Measurements and Results: Acceptable repeat polysomnograms were obtained in 91 subjects (mean study interval: 77 ± 18 {sd} days; range: 31-112 days). There was no significant bias in RDI between study nights using several different RDI definitions including RDI 3% and RDI 4% (apnea or hypopnea events associated with ≥4% O 2 desaturation). Variability between studies estimated using intraclass correlations (ICC) ranged from 0.77 to 0.81. For subjects with a RDI 3%

The advent of large, information-rich data sets partnered with advanced computation has made it increasingly possible to inject life into data through interactive visualization. Brown and colleague...

VanderWeele and Ding introduce the “E-value” as a simple measure of the potential for bias arising from unmeasured confounders in observational studies. Using an example of an observational study o...

e13544 Background: We have developed a drug response assay (ChemoID) that identifies effective chemotherapy against cancer stem cells (CSCs) vs. bulk of tumor cells from of a panel of potential treatments. A prospective study was conducted evaluating the use of the CSC drug response assay in glioblastoma patients treated with standard-of-care. Methods: 41 glioblastoma patients were enrolled in an IRB-approved protocol. Patients were all treated with standard-of-care TMZ plus radiation with or without maximal surgery. Patients were prospectively monitored for tumor response, time to recurrence, progression-free survival (PFS), and overall survival (OS). Results: For every 5% increase in in-vitro CSC cell kill by TMZ, 12-month patient response (non-recurrence of cancer) increased 2-fold, OR=2.2 (p=0.016). Similar associations with the bulk tumor test were seen, OR=2.75 (p=0.07) for each 5% bulk tumor cell kill by TMZ. Combining CSC and bulk tumor assay results in a single model yielded a statistically supported CSC association, OR=2.36 (p=0.036) but a much attenuated remaining bulk tumor association, OR=1.46 (p=0.472). Areas under the curve (AUC) and [sensitivity/specificity] at optimal outpoints (>40% CSC cell kill and >55% bulk tumor cell kill) were AUC=0.989 [Sens=100/Spec=97], 0.972 [100/89] and 0.989 [100/97] for the CSC only, bulk tumor only, and combined models, respectively. Risk categorization of patients was improved by 11% when using the CSC test in conjunction with the bulk test (risk reclassification non-event NRI and overall NRI = 0.111, p=0.030). Median recurrence time was 20 months for patients with a positive (>40% cell kill) CSC test versus only 3 months with a negative CSC test, whereas median recurrence time was 13 months versus 4 months for patients with a positive (>55% cell kill) bulk test versus negative. Similar favorable results for the CSC test were observed for PFS and OS. Results across 14 potential other treatments indicated that 34/41 (83%) and 27/41 (66%) potentially more optimal alternative therapies may have been chosen using CSC results and Bulk results, respectively. Conclusions: The ChemoID assay has the potential to increase the accuracy of bulk tumor assays.

This brief tutorial aims to help clinicians assess the clinical relevance of results from intention-to-treat analyses and decide whether results from additional analyses may be helpful.

432 Background: In clinical trials and clinical practice, tumor response assessment with computed tomography (CT) defines critical end points in patients with metastatic disease treated with systemic agents. Methods to reduce errors and improve efficiency in tumor response assessment could improve patient care. Methods: Eleven readers from 10 different institutions independently categorized tumor response according to three different therapeutic response criteria using paired baseline and initial post-therapy CT studies from 20 randomly selected patients with metastatic renal cell carcinoma treated with sunitinib as part of a completed phase III multi-institutional study. Images were evaluated with a manual tumor response evaluation method (standard-of-care) and with computer-assisted response evaluation (CARE) that included stepwise guidance, interactive error-identification and correction methods, automated tumor metric extraction, calculations, response categorization, and data/image archival. A cross-over design, patient randomization, and two-week washout period were used to reduce recall bias. Comparative effectiveness metrics included error rate and mean patient evaluation time. Results: The standard-of-care method was on average associated with one or more errors in 30.5% (6.1/20) of patients while CARE had a 0.0% (0.0/20) error rate (p

Background— QRS prolongation is associated with adverse outcomes in mostly white populations, but its clinical significance is not well established for other groups. We investigated the association between QRS duration and mortality in African Americans. Methods and Results— We analyzed data from 5146 African Americans in the Jackson Heart Study stratified by QRS duration on baseline 12-lead ECG. We defined QRS prolongation as QRS≥100 ms. We assessed the association between QRS duration and all-cause mortality using Cox proportional hazards models and reported the cumulative incidence of heart failure hospitalization. We identified factors associated with the development of QRS prolongation in patients with normal baseline QRS. At baseline, 30% (n=1528) of participants had QRS prolongation. The cumulative incidences of mortality and heart failure hospitalization were greater with versus without baseline QRS prolongation: 12.6% (95% confidence interval [CI], 11.0–14.4) versus 7.1% (95% CI, 6.3–8.0) and 8.2% (95% CI, 6.9–9.7) versus 4.4% (95% CI, 3.7–5.1), respectively. After risk adjustment, QRS prolongation was associated with increased mortality (hazard ratio, 1.27; 95% CI, 1.03–1.56; P =0.02). There was a linear relationship between QRS duration and mortality (hazard ratio per 10 ms increase, 1.06; 95% CI, 1.01–1.12). Older age, male sex, prior myocardial infarction, lower ejection fraction, left ventricular hypertrophy, and left ventricular dilatation were associated with the development of QRS prolongation. Conclusions— QRS prolongation in African Americans was associated with increased mortality and heart failure hospitalization. Factors associated with developing QRS prolongation included age, male sex, prior myocardial infarction, and left ventricular structural abnormalities.

Objectives: To examine associations between specific inflammatory biomarkers and cognitive function in African Americans (AAs) and European Americans (EAs) with prevalent vascular risk factors. Design: Cross-sectional analysis using generalized estimating equations to account for familial clustering; standardized β-coefficients, adjusted for age, sex, and education are reported. Setting: Community cohort study in Jackson, Mississippi, and Rochester, Minnesota. Participants: Genetic Epidemiology Network of Arteriopathy (GENOA)–Genetics of Microangiopathic Brain Injury (GMBI) Study participants. Measurements: Associations between inflammation (high-sensitivity C-reactive protein (CRP), interleukin (IL)-6, soluble tumor necrosis factor (TNF) receptor 1 and 2 (sTNFR1, sTNFR2)) and cognitive function (global, processing speed, language, memory, and executive function) were examined in AAs and EAs (N = 1,965; aged 26–95, 64% women, 52% AA, 75% with hypertension). Results: In AAs, higher sTNFR2 was associated with poorer cognition in all domains (global: −0.11, P = .009; processing speed: −0.11, P < .001; language: −0.08, P = .002; memory: −0.09, P = .008; executive function: −0.07, P = .03); sTNFR1 was associated with slower processing speed (−0.08, P < .001) and poorer executive function (−0.08, P = .008); higher CRP was associated with slower processing speed (−0.04, P = .024), and higher IL6 was associated with poorer executive function (−0.07, P = .02). In EA, only higher sTNFR1 was associated with slower processing speed (−0.05, P = .007). Associations were not found between cognition and sTNFR2, CRP, or IL6 in EA. Conclusion: In a population with high vascular risk, adverse associations between inflammation and cognitive function were especially apparent in AAs, primarily involving markers of TNFα activity.

The aim of this study is to assess the prevalence and changes over time of ideal Life's Simple Seven (LSS) in African-Americans.Prospective cohort of 5301 African-Americans from the Jackson Heart Study (JHS) from 2000 to 2013. Each of the LSS metrics was categorized as poor, intermediate, or ideal.Among men, the prevalence of having 0, 1, 2, 3, 4, 5, 6, and 7 ideal LSS was 3.3%, 23.0%, 33.5%, 24.7%, 11.6%, 3.6%, 0.3%, and 0%, respectively. Corresponding values for women were 1.7%, 26.3%, 33.1%, 22.8%, 11.9%, 3.7%, 0.6%, and 0%. Prevalence of ideal diet was 0.9%. The proportions of those meeting LSS ideal recommendations for cholesterol and fasting glucose declined from the first through third JHS visits across all age groups, whereas prevalence of ideal BMI declined only in participants40 years at a given visit. Prevalence of ideal blood pressure did not change over time and being ideal on physical activity improved from the first [18.3% (95% CI: 17.3% to 19.3%)] to third visit [24.8% (95% CI: 23.3% to 26.3%)].Our data show a low prevalence of ideal LSS (especially diet, physical activity, and obesity) in the JHS and a slight improvement in adherence to physical activity recommendations over time.

Objective We sought to identify whether stable single nucleotide polymorphisms (SNPs) of various endocrine and immune molecules could be used as biomarkers associated with specific immune alterations and chronic stress measures in normal humans. Methods A total of 207 volunteer participants answered stress questionnaire and gave peripheral blood cells for identification of SNPs in genes coding for glucocorticoid receptor (GR), beta 2 adrenergic receptor (B2AR), interferon-gamma receptors (IFNGR1, IFNGR2), and interleukin-4 receptor (IL4R). Immunoregulatory profiles were measured by flow cytometry and genotyping assays were performed by allelic discrimination real-time PCR. Results Several significant differences were revealed in associations between stress marker and immune indicators based on SNP categories. For instance, Th1 levels of the minor alleles of GR TthIIII (AA) and IFNGR2 Q64R (Arg/Arg) groups were positively associated with chronic stress (PSS) ( p = 0.024 and 0.005, respectively) compared with wild type (WT) and negatively associated with PSS in the heterozygous genotypes of GR BclI and IL4R Ile50Val ( p = 0.040 and p = 0.052, respectively). Treg levels of the minor alleles of BclI (GG) and IFNGR1 T-56C (CC) groups were positively associated with PSS ( p = 0.045 and p = 0.010, respectively) and negatively associated in the minor allele (Val/Val) of IL4R Ile50Va and the heterozygous genotype of IL4R Q576R ( p = 0.041 and p = 0.017, respectively) compared to WT. Conclusion The data support the notion that gene polymorphisms from various components of the psychoneuroendocrine-immune network may be useful as biomarkers to categorize individual stress-associated immune responses.