Search

Background: Midlife cardiovascular risk factors (CVRF) increase dementia risk. Less is known about whether CVRF identified before midlife impact late-life cognition in diverse populations., Methods: Linear regression models examined hypertension, hyperlipidemia, and overweight/obesity at ages 30 to 59 with late-life executive function, semantic memory, verbal episodic memory, and global cognition in a cohort of Asians, blacks, Latinos, and whites (n=1127; mean age=75.8, range=65 to 98). Models adjusted for age at CVRF, age at cognitive assessment, sex, race/ethnicity, participant education, and parental education., Results: Overall, 34% had 1 CVRF at ages 30 to 59; 19% had 2+. Blacks (26%) and Latinos (23%) were more likely to have 2+ CVRF than Asians (14%) or whites (13%). Having 2+ CVRF was associated with lower global cognition [β=-0.33; 95% confidence interval (CI)=-0.45, -0.21], executive function (β=-0.26; 95% CI=-0.39, -0.13), verbal episodic memory (β=-0.34; 95% CI=-0.48, -0.20), and semantic memory (β=-0.20; 95% CI=-0.33, -0.07). Interaction by age (P=0.06) indicated overweight/obesity was negatively associated with executive function at ages 30 to 39 but not at ages 40 to 59. Race/ethnic-specific effects showed disparities in CVRF prevalence impact population disparities in late-life cognition., Conclusion: Being overweight/obese in early adulthood and having 2+ CVRF in early adulthood/midlife are modifiable targets to redress racial/ethnic disparities in cognitive impairment and dementia., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Wild-type transthyretin (ATTRwt) amyloid deposits have been found in the ligamentum flavum of patients undergoing surgery for spinal stenosis. The relationship between ATTRwt and ligamentum flavum thickness is unclear. We used pre-operative magnetic resonance imaging (MRI) to analyze ligamentum flavum thickness in lumbar spinal stenosis patients with and without ATTRwt amyloid., Methods: We retrospectively identified 178 patients who underwent lumbar spine surgery. Ligamentum flavum thickness of 253 specimens was measured on T2-weighted axial MRI. Amyloid presence was confirmed through Congo red staining of specimens, and ATTRwt was confirmed using mass-spectrometry and gene sequencing., Results: Twenty four of the 178 patients (13.5%) were found to have ATTRwt in the ligamentum flavum. Forty ATTRwt specimens and 213 non-ATTRwt specimens were measured. Mean ligamentum flavum thickness was 4.92 (±1.27) mm in the ATTRwt group and 4.00 (±1.21) mm in the non-ATTRwt group (p < 0.01). The ligamentum flavum was thickest at L4-L5, with a thickness of 5.15 (±1.27) mm and 4.23 (±1.29) mm in the ATTRwt and non-ATTRwt group, respectively (p = 0.007). There was a significant difference in ligamentum flavum thickness between ATTRwt and non-ATTRwt case for both patients younger than 70 years (p = 0.016) and those older than 70 years (p = 0.004). ATTRwt patients had greater ligamentum flavum thickness by 0.83 mm (95% confidence interval (CI): 0.41-1.25 mm, p < 0.001) when controlled for age and lumbar level., Conclusion: Patients with ATTRwt had thicker ligamentum flavum compared to patients without ATTRwt. Further studies are needed to investigate the pathophysiology of ATTRwt in ligamentum flavum thickening., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: The authors assessed the cross-sectional association of physical function measures with cognition in the Kaiser Healthy Aging and Diverse Life Experiences Cohort., Methods: Analyses included 1369 participants (24% Asian, 26% Black, 18% Latino, 32% White). Grip strength was measured using a hand-held dynamometer (kilograms) and gait speed was measured over a 4-m walk (seconds/meter). The Spanish and English Neuropsychological Assessment Scales was used to evaluate cognitive domains of executive function, semantic memory, and verbal episodic memory. Physical function measures (per SD) were associated with cognitive test z-scores in linear regression models adjusted for demographic, behavioral, and clinical factors. Racial/ethnic differences were tested using interaction terms and stratification., Results: Stronger grip was associated with better executive function [β=0.10 (95% confidence interval, 0.05-0.15)], semantic memory [β=0.13 (0.09-0.18)] and verbal episodic memory [β=0.07 (0.02-0.13)] with no racial/ethnic differences. Faster gait was associated with better executive function [β=0.29 (0.22-0.36)], semantic memory [β=0.23 (0.16-0.30)], and verbal episodic memory [β=0.20 (0.13-0.27)]; however, the association between gait speed and executive function varied by race/ethnicity with the strongest associations in Asians and Whites., Conclusion: Across race/ethnicity, grip strength and gait speed were associated with cognition with racial/ethnic differences in the association of gait speed and executive function., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

The drug transporter P-glycoprotein (P-gp) is often investigated in drug-interaction studies because the activity is modulated by a wide variety of xenobiotics including drugs, herbal products, and food components. In this study, we tested six common arylsulfonate food dyes-allura red, carmoisine, ponceau 4R, quinolone yellow, sunset yellow, and tartrazine-as activators and inhibitors of P-gp activity in vitro. The dyes were studied as P-gp activators by measuring ATPase activity in P-gp-expressing membranes. Compared to verapamil, a known activator of P-gp, the six food dyes showed no stimulatory activity. The potential for these six food dyes to act as P-gp inhibitors was tested in an intracellular efflux assay with P-gp-expressing cells. Compared to GF120918, a known P-gp inhibitor, there was no inhibitory activity for these six food dyes. The six food dyes tested do not interact with P-gp in vitro and, therefore, are unlikely cause clinical drug-food dye interactions. Further investigation is necessary to determine whether these food dyes could interact with other drug transporters., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Wild-type transthyretin amyloid (ATTRwt) has been noted to deposit in the ligamentum flavum of the spine. Prior studies have focused on ATTRwt in the lumbar region, but studies discussing its presence in other levels of the spine are lacking. We report on the presentation of patients with confirmed amyloid in the cervicothoracic regions and discuss the literature to date., Methods: We retrospectively identified patients at a single institution who underwent surgery for spinal stenosis and had pathologic specimens sent for amyloidosis testing with Congo red staining. ATTRwt was confirmed by the presence of transthyretin amyloid by typing and the absence of mutations in the TTR gene sequence. A final study group of patients with ATTRwt and spinal involvement was established (n = 27)., Results: Of 27 patients with amyloid in the spine, 24 (89%) had amyloid present in the lumbar region, 2 (7%) had amyloid in the cervical region, and 1 (4%) had amyloid in the thoracic region. The median age at which patients in the study underwent surgery was 71 years (interquartile range: 9). Spinal stenosis was the indication for surgery in 26 of 27 (96%) patients. Surgery involved 1 or 2 spinal levels in 24 of 27 (89%) patients., Conclusions: ATTRwt amyloid predominantly deposits in the lumbar region, but it can also be present in the cervical and thoracic regions. While the lumbar regions should remain a focus for evaluation of ATTRwt amyloidosis, the cervicothoracic region should not be ignored., (Copyright © 2020 Elsevier Inc. All rights reserved.)

We examined associations of individual- and neighborhood-level life-course (LC) socioeconomic status (SES) with incident dementia in the Atherosclerosis Risk in Communities cohort. Individual- and neighborhood-level SES were assessed at 3 life epochs (childhood, young adulthood, midlife) via questionnaire (2001-2002) and summarized into LC-SES scores. Dementia was ascertained through 2013 using cognitive exams, telephone interviews, and hospital and death certificate codes. Cox regression was used to estimate hazard ratios of dementia by LC-SES scores in race-specific models. The analyses included data from 12,599 participants (25% Black) in the United States, with a mean age of 54 years and median follow-up of 24 years. Each standard-deviation greater individual LC-SES score was associated with a 14% (hazard ratio (HR) = 0.86, 95% confidence interval (CI): 0.81, 0.92) lower risk of dementia in White and 21% (HR = 0.79, 95% CI: 0.71, 0.87) lower risk in Black participants. Education was removed from the individual LC-SES score and adjusted for separately to assess economic factors of LC-SES. A standard-deviation greater individual LC-SES score, without education, was associated with a 10% (HR = 0.90, 95% CI: 0.84, 0.97) lower dementia risk in White and 15% (HR = 0.85, 95% CI: 0.76, 0.96) lower risk in Black participants. Neighborhood LC-SES was not associated with dementia. We found that individual LC-SES is a risk factor for dementia, whereas neighborhood LC-SES was not associated., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: We assessed cross-sectional differences in sleep quality and risk factors among Asian, Black, Latino, and White participants in the Kaiser Healthy Aging and Diverse Life Experiences (KHANDLE) Study., Methods: KHANDLE enrolled community-dwelling adults aged ≥65 years living in northern California. Participants completed a modified Pittsburgh Sleep Quality Index to measure six sleep components and a global sleep score (scored 0-24). Covariates included age, sex, central adiposity, education, income, alcohol consumption, ever smoking, physical activity, and depression. Ordinal logistic regression was used to model sleep component scores across race/ethnic groups. Linear regression was used to assess racial/ethnic differences in global sleep score and the association between risk factors and global sleep score., Results: 1,664 participants with a mean age of 76 (SD=7) and mean global sleep score of 6 (SD=4) were analyzed. Using Latinos as reference (highest average sleep score), Blacks had an average .96 (.37, 1.54) unit higher global sleep score (worse sleep) while Asians [ β : .04 (-.56, .63)] and Whites [ β : .28 (-.29, .84)] did not significantly differ. Compared with Latinos, Blacks and Asians had greater odds of a worse score on the sleep duration component; Blacks and Whites had greater odds of a worse score on the sleep disturbances component; and, Whites had greater odds of a worse score on the medication component. Risk factors for poor sleep did not differ by race/ethnicity except alcohol consumption (interaction P=.04), which was associated with poor sleep in Blacks only., Conclusions: In this cohort, racial/ethnic differences in sleep quality were common., Competing Interests: Competing Interests: None declared., (Copyright © 2020, Ethnicity & Disease, Inc.)

Introduction: Leisure time activity is associated with better cognitive function but has not been well studied in racially/ethnically diverse cohorts, who may have different access to activities., Methods: Frequency of participation in 10 leisure time activities (eg, reading, attending cultural events) and cognition (executive function, semantic memory, and verbal episodic memory) were assessed at Wave 1 in the Kaiser Healthy Aging and Diverse Life Experiences (KHANDLE) study, a prospective cohort initiated in 2017. Linear regression models adjusted for sociodemographics and depression estimated cross-sectional associations between leisure time activity variety and frequency and cognitive domains overall and by race/ethnicity. Logistic regression models estimated odds of cognitive impairment among those in the lowest quartiles of activity variety and frequency. All models controlled for age, sex, education, income, retirement status, and depression., Results: Higher leisure time activity variety was significantly associated with better cognition for all, except for verbal episodic memory among Asians (β = 0.05, 95% confidence interval [CI]: -0.004, 0.11) and semantic memory among Latinos (β = 0.04, 95% CI: -0.01, 0.08). Low activity variety was associated with nearly three-fold increased odds of cognitive impairment (adjusted odds ratio [OR] = 2.87, 95% CI: 1.77, 4.64). Activity frequency was associated with higher executive function only among whites (β = 0.10, 95% CI: 0.02, 0.18). Patterns by race/ethnicity were not explained by education., Discussion: Engaging in a wider variety of leisure time activities may be more important than frequently participating in fewer activities for cognitive aging in racially/ethnically diverse cohorts., Competing Interests: The authors have no financial interests in the subject matter or findings presented in this study., (© 2020 The Authors. Alzheimer's & Dementia: Translational Research & Clinical Interventions published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Super-intense laser plasma interaction has shown great promise as a platform for next generation particle accelerators and sources for electron, x-rays, ions and neutrons. In particular, when a relativistic intense laser focus interacts with a thin solid density target, ionized electrons are accelerated to near the speed of light (c) within an optical cycle and are pushed in the forward and transverse directions away from focus, carrying a significant portion of the laser energy. These relativistic electrons are effectively collisionless, and their interactions with the ions and surrounding cold electrons are predominantly mediated by collective electromagnetic effects of the resulting currents and charge separation. Thus, a deeper understanding of subsequent high energy ions generated from various mechanisms and their optimization requires knowledge of the relativistic electron dynamics and the fields they produce. In addition to producing MV/m quasi-static fields, accelerating the ions and confining the majority of the electrons near the bulk of the laser target, these relativistic electron currents are subject to plasma instabilities like the Weibel instability as they propagate through the thermal population in the bulk target. In this work, we present high temporal (100 fs) and spatial (1 μm) resolution shadowgraphy video capturing relativistic radial ionization front expansion and the appearance of filamentation radiating from the laser spot within a sub-micron thick liquid sheet target. Filamentation within the region persists for several picoseconds and seeds the eventual recombination and heating dynamics on the nanosecond timescale. A large scale three-dimensional particle-in-cell (PIC) simulation of the interaction revealed the presence of strong magnetic fields characteristic of Weibel Instability, and corroborated the relativistic radial expansion of the ionization front, whose speed was determined to be 0.77c. Both the experimental and simulation results strongly point towards the target field ionization and the outward expanding hot electron current as the cause of the radial expansion.

Objective: We aimed to assess the association between migraine headache and incident dementia., Background: Migraine is a risk factor for white matter hyperintensities and ischemic stroke, which are both associated with increased risk of dementia. However, it is unknown whether migraine is independently associated with dementia., Methods: History of migraine was ascertained via questionnaire. Adjudicated cases of dementia were identified using cognitive tests, neuropsychological exams, and clinician review of suspected cases. Incident dementia was identified using adjudicated cases, follow-up calls, and surveillance of hospital and death codes. We assessed hazards of incident dementia by migraine status. Sex differences were also examined and stratified results were presented., Results: Analysis included 12,495 White and African American participants ages 51-70 with a median follow-up time of 21 years. Prevalence of dementia was 18.5% (1821/9955) among those with no migraine history, 15.8% (196/1243) among those with severe non-migraine heading, and 16.7% (233/1397) among migraineurs. There was no association between migraine and incident dementia [hazard ratio: 1.04 (0.91, 1.20)]. There was also no statistically significant interaction between sex and migraine status on risk of dementia., Conclusion: Despite evidence of brain abnormalities in migraineurs, there was no association between migraine and incident dementia in this prospective cohort., (© 2020 American Headache Society.)

Infections of herpes simplex virus type 1 (HSV-1), cytomegalovirus (CMV), Helicobacter pylori , and Chlamydia pneumoniae may play a role in cognitive decline via systemic inflammation. We hypothesized that Atherosclerosis Risk in Communities study participants who were seropositive in midlife for antibodies to HSV-1, CMV, H pylori , or C pneumoniae would have an accelerated rate of cognitive decline over 20 years. Atherosclerosis Risk in Communities performed a case-cohort study involving a stratified random sample of participants tested for serum immunoglobulin G antibodies to the pathogens of interest. We conducted a longitudinal study using this cohort. Cognitive change was measured using Z scores from the Delayed Word Recall (DWR), Digit Symbol Substitution (DSS), and Word Fluency (WF) Tests administered at visits 2 (1990-1992), 4 (1996-1998), and 5 (2011-2013). Linear regression models with generalized estimating equations and inverse probability of attrition weights were used to evaluate associations between infection and cognitive performance. Four hundred twenty-six participants were analyzed, of which 3% were seronegative for all 4 infections, 14% seropositive for one, 33% and 34% seropositive for 2 and 3, respectively, and 16% seropositive for all infections. At baseline, test scores were significantly lower for participants seropositive for H pylori and C pneumoniae . After baseline covariate adjustment, the rate of decline in DWR, DSS, WF, and global Z scores did not differ significantly by infection status for any of the 4 infections. There was also no significant association between the number of infections for which participants were seropositive and cognitive decline. Our study provides no evidence supporting a longitudinal relationship between seropositivity and cognitive decline.

Background: Abnormal thyroid hormone levels (high or low) and autoimmunity from autoimmune thyroid disease (AITD) may increase dementia risk., Methods: We examined the associations of thyroid dysfunction or possible AITD in 1990 - 1992 with dementia through 2017 in the Atherosclerosis Risk in Communities (ARIC) Neurocognitive Study. Thyroid dysfunction (subclinical and overt hypo- or hyperthyroidism and euthyroidism) was categorized from serum thyroid-stimulating hormone (TSH) and free thyroxine (FT4) cut-points and AITD from anti-thyroid peroxidase (anti-TPO) antibody positivity. Dementia was identified primarily based on cognitive test performance, neuropsychological examinations and clinician review of suspected cases. Additional cases of dementia were ascertained through telephone interviews or relevant hospital and death certificate codes. Cox regression with multivariable adjustment was used for analysis., Results: After exclusions for missing data, 12,481 participants were included in the analysis (mean index exam age 57 ± 5.7 (44% male, 25% black)), and 2,235 incident dementia cases were identified. AITD was not significantly associated with dementia. Subclinical hypothyroidism was associated with a lower risk of dementia (hazard ratio (HR) (95% confidence interval (CI)): 0.74 (0.60 - 0.92)), while overt hyperthyroidism was associated with a higher risk of dementia (HR (95% CI): 1.40 (1.02 - 1.92)) compared to euthyroid participants. Participants with serum FT4 concentrations above the 95th percentile were at an increased risk of dementia compared to those in the middle 90% of FT4 (HR (95% CI): 1.23 (1.02 - 1.48))., Conclusions: Subclinical hypothyroidism was associated with reduced risk of dementia, whereas overt hyperthyroidism, particularly very elevated FT4, was associated with increased risk of dementia. The association between subclinical hypothyroidism and reduced risk of dementia cannot be explained, but may have been an artifact due to change. By extrapolation, effective treatment of overt hyperthyroidism may modestly reduce dementia risk in older adults., Competing Interests: Conflict of Interest The authors have no conflict of interest.

Geographic differences in cardiovascular disease (CVD) mortality among African Americans (AAs) are well-established, but not well-characterized. Using the Minnesota Heart Survey (MHS) and Atherosclerosis Risk in Communities (ARIC) Study, we aimed to assess whether CVD risk factors drive geographic disparities in CVD mortality among AAs. ARIC risk factors were measured between1987-1989 from a population-based sample of AAs, aged 45 to 64 years, living in Jackson, MS and Forsyth County, NC. Similar measures were made at MHS baseline, 1985, in AAs from Minneapolis-St. Paul, MN. CVD mortality was identified using ICD codes for underlying cause of death. We compared MHS and ARIC on CVD death rates using Poisson regression, risk factor prevalences, and hazard ratios using Cox regression. After CVD risk factor adjustment, AA men in MHS had 3.4 (95% CI: 2.1, 4.7) CVD deaths per 1000 person-years vs 9.9 (95% CI: 8.7, 11.1) in ARIC. AA women in MHS had 2.7 (95% CI: 1.8, 3.6) CVD deaths per 1000 person-years vs 6.7 (95% CI: 6.0, 7.4) in ARIC. A 2-fold higher CVD mortality rate remained in ARIC vs MHS after additional adjustment for education and income. ARIC had higher total cholesterol, hypertension, diabetes, and BMI, as well as less education and income than MHS. Risk factor hazard ratios of CVD death did not differ. The CVD death rate was lower in AAs in Minnesota (MHS) than AAs in the Southeast (ARIC). While our findings support maintaining low risk for CVD prevention, differences in CVD mortality reflect unidentified geographic variation., Competing Interests: Competing Interests: None declared.

A sex × diabetes interaction in cardiovascular disease (CVD) has been established among white persons; however, it is unknown whether this interaction occurs among African Americans. We hypothesized that there was a multiplicative sex × diabetes interaction for CVD among African Americans participating in the Atherosclerosis Risk in Communities Study (1987-2013). Race-specific Cox models were run in three stages: Stage 1 examined baseline diabetes status; stage 2 examined baseline diabetes status with the competing risk of non-CVD death; and stage 3 examined time-varying diabetes status with a competing risk of non-CVD death. There were 1,073 incident CVD events among 3,767 African Americans and 2,475 among 10,291 white persons. Among African Americans, in stage 1 analysis, the hazard ratio for women with diabetes was 2.3 (95% confidence interval (CI): 2.0, 2.7) compared with women without diabetes after adjustment for age, and the corresponding hazard ratio for men was 1.8 (95% CI: 1.5, 2.1) (P for interaction = 0.014). After full adjustment, the diabetes hazard ratio was attenuated to 2.0 (95% CI: 1.8, 2.3) among women and remained 1.8 (95% CI: 1.5, 2.1) for men (P for interaction = 0.058). A synergistic influence on CVD risk between being a black woman and having diabetes was consistent across stage 2 and stage 3 analyses, with marginally significant interaction, mirroring sex differences seen in whites.

Background: Few studies have addressed retention of minorities, particularly African Americans, in longitudinal research. Our aim was to determine whether there was differential retention between African Americans and Whites in the ARIC cohort and identify cardiovascular disease (CVD) risk factors and indicators of socioeconomic status (SES) associated with these retention differences., Methods: 15,688 participants, 27% African American and 73% White, were included from baseline, 1987-1989, and classified as having died, lost or withdrew from study contact, or remained active in study calls through 2013. Life tables were created illustrating retention patterns stratified by race, from baseline through visit 5, 2011-2013. Prevalence tables stratified by race, participation status, and center were created to examine CVD risk factors and SES at baseline and visit 5., Results: 54% of African Americans compared with 62% of Whites were still in follow-up by 2013. This difference was due to an 8% higher cumulative incidence of death among African Americans. Those who remained in follow-up had the lowest baseline CVD risk factors and better SES, followed by those who were lost/withdrew, then those who died. Whites had lower levels of most CVD risk factors and higher SES than African Americans overall at baseline and visit 5; though, the magnitude of visit 5 differences was less., Conclusions: In the ARIC cohort, retention differed among African Americans and Whites, but related more to mortality differences than dropping-out. Additional research is needed to better characterize the factors contributing to minority participants' recruitment and retention in longitudinal research., Competing Interests: Conflicts of Interest: None declared.

We report on the recently completed 400 TW upgrade to the Scarlet laser at The Ohio State University. Scarlet is a Ti:sapphire-based ultrashort pulse system that delivers >10  J in 30 fs pulses to a 2 μm full width at half-maximum focal spot, resulting in intensities exceeding 5×10 21   W/cm 2 . The laser fires at a repetition rate of once per minute and is equipped with a suite of on-demand and on-shot diagnostics detailed here, allowing for rapid collection of experimental statistics. As part of the upgrade, the entire laser system has been redesigned to facilitate consistent, characterized high intensity data collection at high repetition rates. The design and functionality of the laser and target chambers are described along with initial data from commissioning experimental shots.

Introduction: Epidemiological studies generally have not found plasma total fibrinogen to be a risk factor for venous thromboembolism (VTE), but several have reported associations between variants in the fibrinogen gamma gene (FGG) and VTE. A case-control study in whites suggested plasma γ' fibrinogen concentration may be associated inversely with VTE, but this was not replicated in African Americans., Objective: To examine the prospective association between γ' fibrinogen concentrations and occurrence of VTE., Methods: We used the Longitudinal Investigation of Thromboembolism Etiology (LITE), involving two pooled population-based cohorts in the United States including 16,234 participants. The cohorts comprised white and African American men and women, aged 50years and older at study onset in the early 1990s. We identified VTEs during follow-up and documented they met standardized diagnostic criteria., Results: During two decades of follow-up, neither γ' fibrinogen nor total fibrinogen nor their ratio was associated with VTE overall (n=521 VTEs), in subgroups defined by race, or in other subgroups. In both race groups, the minor allele of FGG rs2066865 was associated with lower γ' fibrinogen concentrations, but this allele was not associated with VTE., Conclusions: A lower plasma concentration of γ' fibrinogen in healthy adults does not appear to increase VTE risk., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

We report on the first successful proof-of-principle experiment to manipulate laser-matter interactions on microscales using highly ordered Si microwire arrays. The interaction of a high-contrast short-pulse laser with a flat target via periodic Si microwires yields a substantial enhancement in both the total and cutoff energies of the produced electron beam. The self-generated electric and magnetic fields behave as an electromagnetic lens that confines and guides electrons between the microwires as they acquire relativistic energies via direct laser acceleration.

Background and Aims: An elevated plasma concentration of intrinsic coagulation factor XI is a risk factor for venous thromboembolism, but its role in the etiology of atherothrombotic outcomes is uncertain. We examined the association of factor XI with incident stroke and coronary heart disease in the prospective Atherosclerosis Risk in Communities (ARIC) Study., Methods: We measured factor XI on plasma samples collected in 1993-1995 from middle-aged adults (n = 11,439), who were followed through 2012 for incident cardiovascular events., Results: Over a median of 18 years of follow-up (max = 20 years), 722 participants had incident stroke events (631 ischemic and 91 hemorrhagic) and 1776 had incident coronary events. Although there were weak positive associations between factor XI and total, ischemic, cardioembolic, and nonlacunar stroke, when adjusted for demographics, further adjustment for other stroke risk factors eliminated the associations. Similarly, there was no independent association of factor XI with incident coronary heart disease events., Conclusion: A higher basal factor XI concentration in the general population was not a risk marker for stroke or coronary heart disease., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Introduction: Plasma D-dimer is a useful clinical test for acute venous thromboembolism (VTE), and concentrations remain higher in VTE patients after treatment than in controls. Yet, evidence is limited on whether higher basal D-dimer concentrations in the general population are associated with greater risk of first VTE., Objective: To assess the prospective association between D-dimer and incident VTE over a long follow-up., Methods: We measured plasma D-dimer in 12,097 participants, initially free of VTE, in the Atherosclerosis Risk in Communities Study. Over a median follow-up of 17years, we identified 521 VTEs. We calculated hazard ratios of VTE using proportional hazards regression., Results: The age, race, and sex adjusted hazard ratios of VTE across quintiles of D-dimer were 1, 1.5, 1.8, 2.1, and 3.2 (p for trend <0.0001). For the first 10years of follow-up, the hazard ratio for the highest versus lowest quintile was 3.5, and was 2.9 after 10years. In both whites and African Americans, VTE risk remained strongly associated with D-dimer after further adjustment for diabetes, body mass index, kidney function, and several thrombophilia genetic markers. D-dimer was associated with both unprovoked and provoked VTE, but more strongly with unprovoked., Conclusions: A higher basal level of plasma D-dimer in the general population, presumably reflecting a predisposition to thrombosis, is a strong, long-term risk factor for a first VTE., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

The quality of x-ray spectra and images obtained from plasmas with spherically bent crystals depends in part on the crystal's x-ray diffraction across the entire crystal surface. We employ the energy selectivity and high intensity of synchrotron radiation to examine typical spherical crystals from alpha-quartz for their diffraction quality, in a perpendicular geometry that is particularly convenient to examine sagittal focusing. The crystal's local diffraction is not ideal: the most noticeable problems come from isolated regions that so far have failed to correlate with visible imperfections. Excluding diffraction from such problem spots has little effect on the focus beyond a decrease in background.

In this study, the first mechanism-based monoclonal antibodies have been produced that recognize and differentiate diethoxy- and monoethoxyphosphorylated serine residues. Haptens were synthesized as the stable phosphonate form of phosphoserine esters to improve the immunoresponse. Following condensation with a glutaric anhydride to link the phosphoserine moieties to carrier protein, the hapten densities attached to bovine serum albumin and keyhole limpet henocyanin were determined by partial trypsin digestion and MALDI mass spectrometry, and confirmed using a fluorescent assay (FITC) to quantify unmodified lysine residues. The conjugation reactions were pH optimized to improve hapten density. Screening of subclones led to the identification of two monoclonal antibodies: (a) N257/25.11 that specifically recognizes (EtO)2P(O)-Ser as the phosphylated or inhibited form, and (b) N262/16 that recognizes (EtO)(HO)P(O)-Ser as the 'aged' form. Analysis of blood samples treated with paraoxon (EtO)2P(O)-OPhNO2 showed a concentration dependent recognition of the phosphylated form., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Organophosphate (OP) compounds are used as insecticides, acaricides, and chemical agents and share a common neurotoxic mechanism of action. The biochemical alterations leading to many of the deleterious effects have been studied in neuronal cell lines, however, non-neuronal toxic effects of OPs are far less well characterized in vitro, and specifically in cell lines representing oral routes of exposure. To address this void, the human salivary gland (HSG) cell line, representing likely interactions in the oral cavity, was exposed to the representative OP paraoxon (PX; O,O-diethyl-p-nitrophenoxy phosphate) over a range of concentrations (0.01-100 μM) and analyzed for cytotoxicity. PX induced cytotoxicity in HSG cells at most of the exposure concentrations as revealed by MTT assay, however, the release of LDH only occurred at the highest concentration of PX tested (100 μM) at 48 h. Slight increases in cellular ATP levels were measured in PX-exposed (10 μM) HSG cells at 24 h. Exposing HSG cells to 10 μM PX also led to an increase in DNA fragmentation prior to loss of cellular membrane integrity implicating reactive oxygen species (ROS) as a trigger of toxicity. The ROS genes gss, gstm2, gstt2 and sod2 were upregulated, and the presence of superoxide following 10 μM PX exposure was determined via dihydroethidium fluorescence studies further implicating PX-induced oxidative stress in HSG cells., (Published by Elsevier Ltd.)

Isoxazole-1,4-dihydropyridines (IDHPs) were tethered to fluorescent moieties using double activation via a lanthanide assisted Weinreb amidation. IDHP-fluorophore conjugate 3c exhibits the highest binding to date for IDHPs at the multidrug-resistance transporter (MDR-1), and IDHP-fluorophore conjugates 3c and 7 distribute selectively in SH-SY5Y cells. A homology model for IDHP binding at MDR-1 is presented which represents our current working hypothesis., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Objectives: The Society of Thoracic Surgeons Adult Cardiac Surgery Database has been linked to the Social Security Death Master File to verify "life status" and evaluate long-term surgical outcomes. The objective of this study is explore practical applications of the linkage of the Society of Thoracic Surgeons Adult Cardiac Surgery Database to Social Securtiy Death Master File, including the use of the Social Securtiy Death Master File to examine the accuracy of the Society of Thoracic Surgeons 30-day mortality data., Methods: On January 1, 2008, the Society of Thoracic Surgeons Adult Cardiac Surgery Database began collecting Social Security numbers in its new version 2.61. This study includes all Society of Thoracic Surgeons Adult Cardiac Surgery Database records for operations with nonmissing Social Security numbers between January 1, 2008, and December 31, 2010, inclusive. To match records between the Society of Thoracic Surgeons Adult Cardiac Surgery Database and the Social Security Death Master File, we used a combined probabilistic and deterministic matching rule with reported high sensitivity and nearly perfect specificity., Results: Between January 1, 2008, and December 31, 2010, the Society of Thoracic Surgeons Adult Cardiac Surgery Database collected data for 870,406 operations. Social Security numbers were available for 541,953 operations and unavailable for 328,453 operations. According to the Society of Thoracic Surgeons Adult Cardiac Surgery Database, the 30-day mortality rate was 17,757/541,953 = 3.3%. Linkage to the Social Security Death Master File identified 16,565 cases of suspected 30-day deaths (3.1%). Of these, 14,983 were recorded as 30-day deaths in the Society of Thoracic Surgeons database (relative sensitivity = 90.4%). Relative sensitivity was 98.8% (12,863/13,014) for suspected 30-day deaths occurring before discharge and 59.7% (2120/3551) for suspected 30-day deaths occurring after discharge., Conclusions: Linkage to the Social Security Death Master File confirms the accuracy of data describing "mortality within 30 days of surgery" in the Society of Thoracic Surgeons Adult Cardiac Surgery Database. The Society of Thoracic Surgeons and Social Security Death Master File link reveals that capture of 30-day deaths occurring before discharge is highly accurate, and that these in-hospital deaths represent the majority (79% [13,014/16,565]) of all 30-day deaths. Capture of the remaining 30-day deaths occurring after discharge is less complete and needs improvement. Efforts continue to encourage Society of Thoracic Surgeons Database participants to submit Social Security numbers to the Database, thereby enhancing accurate determination of 30-day life status. The Society of Thoracic Surgeons and Social Security Death Master File linkage can facilitate ongoing refinement of mortality reporting., (Copyright © 2013 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.)

Organic impurities in compound libraries are known to often cause false-positive signals in screening campaigns for new leads, but organic impurities do not fully account for all false-positive results. We discovered inorganic impurities in our screening library that can also cause positive signals for a variety of targets and/or readout systems, including biochemical and biosensor assays. We investigated in depth the example of zinc for a specific project and in retrospect in various HTS screens at Roche and propose a straightforward counter screen using the chelator TPEN to rule out inhibition caused by zinc.

Background: Mitral valve (MV) repair is performed with less frequency than MV replacement in older persons, with referral often delayed until symptoms are severe. Surgical practice in this population remains inconsistent in the absence of national MV repair outcomes. The goal of this study was to assess durability and longitudinal outcomes after isolated primary MV repair in patients aged 65 years or more., Methods: We linked clinical data from The Society of Thoracic Surgeons adult cardiac surgery database (STS) to longitudinal claims data from the Centers for Medicare and Medicaid Services (CMS). Between January 1991 and December 2007, we identified 14,604 isolated nonemergent primary MV repair operations in STS-CMS data. These were longitudinally examined for mortality, mitral reoperation, and readmissions for heart failure, bleeding, and stroke. Predictors of 5-year death after MV repair were identified using Cox proportional hazard modeling., Results: The study cohort had a mean age of 73.3±5.5 years, ejection fraction 54.0%±12.9%; 55.8% (8,148 of 14,604) were female; and 8.4% (1,233 of 14,604) were non-Caucasian. Operative mortality was 2.59% (378 of 14,604). Mean follow-up was 5.9±3.9 years (range, 1.0 to 18.0). Survival during follow-up was 74.9% (10,934 of 14,604). The number of observed events for mitral reoperation, heart failure, bleeding, and stroke were 552 of 14,604 (3.7%), 2,681 of 14,604 (18.4%), 1,051 of 14,604 (7.2%), and 1,131 of 14,604 (7.7%), respectively. The 10-year Kaplan-Meier event rates for mitral reoperation, heart failure, bleeding, and stroke were 6.2%, 30.1%, 15.3%, and 16.4%, respectively. The 10-year actuarial survival of 57.4% was equivalent to the matched US population., Conclusions: Utilizing linked STS and CMS databases, we demonstrate that MV repair is a safe and durable long-term option for older patients. Survival restored to the normal population suggests repair may suppress the longitudinal impact of mitral regurgitation in the elderly and that the practice of delayed referral should be reevaluated. These data provide a contemporary longitudinal benchmark of MV repair outcomes., (Copyright © 2012 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Hydrozirconation of 1-hexyne, the addition to in situ prepared N-acyliminium species, and ring-closing metathesis (RCM) were key steps in the preparation of a tricyclic isoindolinone scaffold. An unusual alkene isomerization process during the RCM was identified and studied in some detail. Chemical diversification for library synthesis was achieved by a subsequent alkene epoxidation and zinc-mediated aminolysis reaction. The resulting library products provided selective hits among a large number of high-throughput screens reported in PubChem, thus illustrating the utility of the novel scaffold.

Background: Long-term evaluation of cardiothoracic surgical outcomes is a major goal of The Society of Thoracic Surgeons (STS). Linking the STS Database to the Social Security Death Master File (SSDMF) allows for the verification of "life status." This study demonstrates the feasibility of linking the STS Database to the SSDMF and examines longitudinal survival after cardiac operations., Methods: For all operations in the STS Adult Cardiac Surgery Database performed in 2008 in patients with an available Social Security Number, the SSDMF was searched for a matching Social Security Number. Survival probabilities at 30 days and 1 year were estimated for nine common operations., Results: A Social Security Number was available for 101,188 patients undergoing isolated coronary artery bypass grafting, 12,336 patients undergoing isolated aortic valve replacement, and 6,085 patients undergoing isolated mitral valve operations. One-year survival for isolated coronary artery bypass grafting was 88.9% (6,529 of 7,344) with all vein grafts, 95.2% (84,696 of 88,966) with a single mammary artery graft, 97.4% (4,422 of 4,540) with bilateral mammary artery grafts, and 95.6% (7,543 of 7,890) with all arterial grafts. One-year survival was 92.4% (11,398 of 12,336) for isolated aortic valve replacement (95.6% [2,109 of 2,206] with mechanical prosthesis and 91.7% [9,289 of 10,130] with biologic prosthesis), 86.5% (2,312 of 2,674) for isolated mitral valve replacement (91.7% [923 of 1,006] with mechanical prosthesis and 83.3% [1,389 of 1,668] with biologic prosthesis), and 96.0% (3,275 of 3,411) for isolated mitral valve repair., Conclusions: Successful linkage to the SSDMF has substantially increased the power of the STS Database. These longitudinal survival data from this large multi-institutional study provide reassurance about the durability and long-term benefits of cardiac operations and constitute a contemporary benchmark for survival after cardiac operations., (Copyright © 2011 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Protein kinase D (PKD) is a member of a novel family of serine/threonine kinases that regulate fundamental cellular processes. PKD is implicated in the pathogenesis of several diseases, including cancer. Progress in understanding the biological functions and therapeutic potential of PKD has been hampered by the lack of specific inhibitors. The benzoxoloazepinolone CID755673 was recently identified as the first potent and selective PKD inhibitor. The study of structure-activity relationships (SAR) of this lead structure led to further improvements in PKD1 potency. We describe herein the synthesis and biological evaluation of novel benzothienothiazepinone analogs. We achieved a ten-fold increase in the in vitro PKD1 inhibitory potency for the second generation lead kb-NB142-70 and accomplished a transition to an almost equally potent novel pyrimidine scaffold, while maintaining excellent target selectivity. These promising results will guide the design of pharmacological tools to dissect PKD function and pave the way for the development of potential anti-cancer agents.

Protein kinase D (PKD) belongs to a family of serine/threonine kinases that play an important role in basic cellular processes and are implicated in the pathogenesis of several diseases. Progress in our understanding of the biological functions of PKD has been limited due to the lack of a PKD-specific inhibitor. The benzoxoloazepinolone CID755673 was recently reported as the first potent and kinase-selective inhibitor for this enzyme. For structure-activity analysis purposes, a series of analogs was prepared and their in vitro inhibitory potency evaluated.

Protein kinase D is a novel family of serine/threonine kinases and diacylglycerol receptors that belongs to the calcium/calmodulin-dependent kinase superfamily. Evidence has established that specific PKD isoforms are dysregulated in several cancer types, and PKD involvement has been documented in a variety of cellular processes important to cancer development, including cell growth, apoptosis, motility, and angiogenesis. In light of this, there has been a recent surge in the development of novel chemical inhibitors of PKD. This review focuses on the potential of PKD as a chemotherapeutic target in cancer treatment and highlights important recent advances in the development of PKD inhibitors., (Copyright © 2010 Elsevier B.V. All rights reserved.)

SH-SY5Y neuroblastoma cells were examined to determine changes in protein expression following exposure to the organophosphate paraoxon (O,O-diethyl-p-nitrophenoxy phosphate). Exposure of SH-SY5Y cells to paraoxon (20 μM) for 48 h showed no significant change in cell viability as established using an MTT assay. Protein expression changes from the paraoxon-treated SH-SY5Y cells were determined using a comparative, subproteome approach by fractionation into cytosolic, membrane, nuclear, and cytoskeletal fractions. The fractionated proteins were separated by 2D-PAGE, identified by MALDI-TOF mass spectrometry, and expression changes determined by densitometry. Over 400 proteins were separated from the four fractions, and 16 proteins were identified with altered expression ≥1.3-fold including heat shock protein 90 (-1.3-fold), heterogeneous nuclear ribonucleoprotein C (+2.8-fold), and H(+) transporting ATP synthase beta chain (-3.1-fold). Western blot analysis conducted on total protein isolates confirmed the expression changes in these three proteins.

Organophosphate pesticides (OPs) are environmental toxicants known to inhibit the catalytic activity of acetylcholinesterase (AChE) resulting in hypercholinergic toxicity symptoms. In developing embryos, OPs have been hypothesized to affect both cholinergic and non-cholinergic pathways. In order to understand the neurological pathways affected by OP exposure during embryogenesis, we developed a subacute model of OP developmental exposure in zebrafish by exposing embryos to a dose of the OP metabolite chlorpyrifos-oxon (CPO) that is non-lethal and significantly inhibited AChE enzymatic activity compared to control embryos (43% at 1 day post-fertilization (dpf) and 11% at 2dpf). Phenotypic analysis of CPO-exposed embryos demonstrated that embryonic growth, as analyzed by gross morphology, was normal in 85% of treated embryos. Muscle fiber formation was similar to control embryos as analyzed by birefringence, and nicotinic acetylcholine receptor (nAChR) cluster formation was quantitatively similar to control embryos as analyzed by α-bungarotoxin staining. These results indicate that partial AChE activity during the early days of zebrafish development is sufficient for general development, muscle fiber, and nAChR development. Rohon-Beard (RB) sensory neurons exhibited aberrant peripheral axon extension and gene expression profiling suggests that several genes responsible for RB neurogenesis are down-regulated. Stability of CPO in egg water at 28.5 °C was determined by HPLC-UV-MS analysis which revealed that the CPO concentration used in our studies hydrolyzes in egg water with a half-life of 1 day. The result that developmental CPO exposure affected RB neurogenesis without affecting muscle fiber or nAChR cluster formation demonstrates that zebrafish are a strong model system for characterizing subtle neurological pathologies resulting from environmental toxicants., (Published by Elsevier B.V.)

Background: The Centers for Medicare and Medicaid Services (CMS) Medicare database complements The Society of Thoracic Surgeons (STS) database by providing information about long-term outcomes and cost. This study demonstrates the feasibility of linking STS data to CMS data and examines the penetration, completeness, and representativeness of the STS database., Methods: Using variables common to both STS and CMS databases, STS operations were linked to CMS data for all CMS coronary artery bypass graft surgery (CABG) hospitalizations discharged between 2000 and 2007, inclusive. For each CMS CABG hospitalization, it was determined whether a matching STS record existed., Results: Center-level penetration (number of CMS sites with at least one matched STS participant divided by the total number of CMS CABG sites) increased from 45% to 78%. In 2007, 854 of 1,101 CMS CABG sites (78%) were linked to an STS site. Patient-level penetration (number of CMS CABG hospitalizations done at STS sites divided by the total number of CMS CABG hospitalizations) increased from 51% to 84%. In 2007, 94,409 of 111,967 CMS CABG hospitalizations (84%) were at an STS site. Completeness of case inclusion at STS sites (number of CMS CABG cases at STS sites linked to STS records divided by the total number of CMS CABG cases at STS sites) increased from 88% to 97%. In 2007, 88,857 of 91,363 CMS CABG hospitalizations at STS sites (97%) were linked to an STS record., Conclusions: The successful linking of STS and CMS databases demonstrates high and increasing penetration and completeness of the STS database. Linking STS and CMS data will facilitate studying long-term outcomes of cardiothoracic surgery., (Copyright © 2010 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

The stability, hydrolysis, and uptake of the organophosphates methyl parathion and methyl paraoxon were investigated in SH-SY5Y cells. The stabilities of ((14)CH(3)O)(2)-methyl parathion ((14)C-MPS) and ((14)CH(3)O)(2)-methyl paraoxon ((14)C-MPO) at 1 microM in culture media had similar half-lives of 91.7 and 101.9 h, respectively. However, 100 microM MPO caused >95% cytotoxicity at 24 h, whereas 100 microM MPS caused 4-5% cytotoxicity at 24 h ( approximately 60% cytotoxicity at 48 h). Greater radioactivity was detected inside cells treated with MPO as compared to MPS, although >80% of the total MPO uptake was primarily dimethyl phosphate (DMP). Maximum uptake was reached after 48 h of (14)C-MPS or (14)C-MPO exposure with total uptakes of 1.19 and 1.76 nM/10(6) cells for MPS and MPO, respectively. The amounts of MPS and MPO detected in the cytosol after 48 h of exposure time were 0.54 and 0.37 nM/10(6) cells, respectively.

Noncompaction of the left ventricle is a rare congenital cardiomyopathy characterized by prematurely arrested compaction of the endocardial and myocardial fibers. Although systolic heart failure is assured, treatment has been traditionally limited to palliative medical therapy or transplantation. We present the first report of long-term clinical and echocardiographic follow-up (50 months) showing sustained myocardial recovery after the use of mitral valve annuloplasty as the primary treatment for severe mitral regurgitation associated with left ventricular noncompaction., (Copyright (c) 2010 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Left ventricular outflow tract obstruction caused by a malpositioned prosthetic mechanical mitral valve has not been reported to date. In two cases of mitral valve replacement, the sewing ring was sutured to the mitral valve leaflet instead of the annulus, resulting in the ventricularization of a portion of the valve and partial obstruction of the outflow tract. Re-replacing the valve with the same type of mechanical valve, but within the annular plane, eliminated the obstruction.

The regioselective palladium-catalyzed cross-coupling reactions of 2,4,7-trichloroquinazoline with various aryl- and heteroarylboronic acids are reported. An efficient, sequential strategy was developed that provides access to novel, functionalized heterocycles.

Objective: Organophosphate (OP) insecticides continue to be used to control insect pests. Acute and chronic exposures to OP insecticides have been documented to cause adverse health effects, but few OP-adducted proteins have been correlated with these illnesses at the molecular level. Our aim was to review the literature covering the current state of the art in mass spectrometry (MS) used to identify OP protein biomarkers., Data Sources and Extraction: We identified general and specific research reports related to OP insecticides, OP toxicity, OP structure, and protein MS by searching PubMed and Chemical Abstracts for articles published before December 2008., Data Synthesis: A number of OP-based insecticides share common structural elements that result in predictable OP-protein adducts. The resultant OP-protein adducts show an increase in molecular mass that can be identified by MS and correlated with the OP agent. Customized OP-containing probes have also been used to tag and identify protein targets that can be identified by MS., Conclusions: MS is a useful and emerging tool for the identification of proteins that are modified by activated organophosphate insecticides. MS can characterize the structure of the OP adduct and also the specific amino acid residue that forms the key bond with the OP. Each protein that is modified in a unique way by an OP represents a unique molecular biomarker that with further research can lead to new correlations with exposure.

Multiple tissue interactions and signaling within the pharyngeal arches are required for development of the craniofacial skeleton. Here, we focus on the role of the transcription factor prdm1a in the differentiation of the posterior skeleton. prdm1a is expressed in the presumptive pharyngeal arch region and later in an endodermal pouch, the otic vesicle, and pharyngeal teeth. prdm1a mutants display a reduction in pharyngeal arch markers, a loss of posterior ceratobranchial cartilages, and a reduction in most neural crest-derived dermal bones. This is likely caused by a decrease in the number of proliferating cells but not an increase in cell death. Finally, a reduction in two key developmental signaling pathways, Fgf and retinoic acid, alters prdm1a expression, suggesting that prdm1a expression is mediated by these signaling pathways to pattern the posterior craniofacial skeleton. Together, these results indicate an essential role for prdm1a in the development of the zebrafish craniofacial skeleton.

Patients with mitral regurgitation caused by posterior leaflet prolapse are ideal candidates for valve repair, yet all too often these patients receive prosthetic replacement. Surgeon discomfort with available repair techniques is often cited as the reason for this suboptimal result. The dissemination of simpler repair techniques might increase the proportion of patients receiving mitral valve repair rather than replacement. Triangular posterior leaflet resection is an easy, effective and durable method for correcting posterior leaflet prolapse. The combination of triangular resection and annuloplasty is an excellent option for mitral valve repair in most patients with posterior leaflet prolapse.

In patients with degenerative mitral valve disease and tall leaflets, systolic anterior motion after mitral valve repair is generally avoided by use of a sliding posterior leaflet repair technique with an annuloplasty of appropriate size. Occasionally, in spite of these maneuvers, systolic anterior motion occurs intraoperatively after discontinuing cardiopulmonary bypass. In such cases, posterior leaflet shortening is a simple option that effectively moves the coaptation point of the mitral leaflets posteriorly, and eliminates left ventricular outflow tract obstruction caused by systolic anterior motion.

Objective: The study objective was to identify characteristics differentiating patients undergoing valve replacement versus valve repair for degenerative mitral valve disease and to use this information to compare survival and reoperation after each procedure., Methods: From 1985 to 2005, 3286 patients underwent isolated primary operation for degenerative mitral valve disease. Valve repair was performed in 3051 patients (93%), and valve replacement was performed in 235 patients (7.2%). A propensity model and score developed for fair comparison of outcomes yielded 195 matched pairs., Results: Patients undergoing replacement were older (70 +/- 12 years vs 57 +/- 13 years) and had more complex valvar pathology, symptoms, and left ventricular dysfunction. Thus, the characteristics of the propensity-matched patients undergoing repair more resembled those of the patients undergoing replacement (older, complex valvar pathology) than patients undergoing typical repair. Eight patients died in the hospital (0.26%) after repair and 5 patients (2.1%) died after replacement (P = .001). Unadjusted survival at 5, 10, and 15 years was 95%, 87%, and 68% after repair and 80%, 60%, and 44% after replacement, respectively (P < .0001); however, among propensity-matched patients, survival was similar (P = .8): 86% versus 83% at 5 years, 63% versus 62% at 10 years, and 43% versus 48% at 15 years. Freedom from reoperation among propensity-matched patients was 94% at 5 and 10 years after repair and 95% and 92% at 5 and 10 years after replacement, respectively (P = .6)., Conclusion: It is reasonable to perform valve repair in elderly patients with complex degenerative mitral valve pathology because it can eliminate the need for anticoagulation and risk of prosthesis-related complications. However, when valve pathology is so complex that repair is infeasible, this study demonstrates that valve replacement does not diminish long-term outcomes.