Faculty Bibliography

To assess the directionality of the association between physical and cognitive decline in later life, we compared patterns of decline in performance across groups defined by baseline presence of cognitive and/or physical impairment [none (n = 217); physical only (n = 169); cognitive only (n = 158), or both (n = 220)] in a large sample of participants in a cognitive aging study at the Knight Alzheimer's Disease Research Center at Washington University in St. Louis who were followed for up to 8 years (3,079 observations). Rates of decline reached 20% for physical performance and varied across cognitive tests (global, memory, speed, executive function, and visuospatial skills). We found that physical decline was better predicted by baseline cognitive impairment (slope = -1.22, p<0.001), with baseline physical impairment not contributing to further decline in physical performance (slope = -0.25, p = 0.294). In turn, baseline physical impairment was only marginally associated with rate of cognitive decline across various cognitive domains. The cognitive-functional association is likely to operate in the direction of cognitive impairment to physical decline although physical impairment may also play a role in cognitive decline/dementia. Interventions to prevent further functional decline and development of disability and complete dependence may benefit if targeted to individuals with cognitive impairment who are at increased risk.

Myocardial necrosis in the perioperative period of noncardiac surgery is associated with short-term mortality, but long-term outcomes have not been characterized. We investigated the association between perioperative troponin elevation and long-term mortality in a retrospective study of consecutive subjects who underwent hip, knee, and spine surgery. Perioperative myocardial necrosis and International Classification of Disease, Ninth Revision-coded myocardial infarction (MI) were recorded. Long-term survival was assessed using the Social Security Death Index database. Logistic regression models were used to identify independent predictors of long-term mortality. A total of 3,050 subjects underwent surgery. Mean age was 60.8 years, and 59% were women. Postoperative troponin was measured in 1,055 subjects (34.6%). Myocardial necrosis occurred in 179 cases (5.9%), and MI was coded in 20 (0.7%). Over 9,015 patient-years of follow-up, 111 deaths (3.6%) occurred. Long-term mortality was 16.8% in subjects with myocardial necrosis and 5.8% with a troponin in the normal range. Perioperative troponin elevation (hazard ratio 2.33, 95% confidence interval 1.33 to 4.10) and coded postoperative MI (adjusted hazard ratio 3.51, 95% confidence interval 1.44 to 8.53) were significantly associated with long-term mortality after multivariable adjustment. After excluding patients with coronary artery disease and renal dysfunction, myocardial necrosis remained associated with long-term mortality. In conclusion, postoperative myocardial necrosis is common after orthopedic surgery. Myocardial necrosis is independently associated with long-term mortality at 3 years and may be used to identify patients at higher risk for events who may benefit from aggressive management of cardiovascular risk factors.

The purpose of this study was to evaluate the efficacy of Mucograft (MG; a porcine-derived purified collagen membrane) to increase the thickness and height of the buccal soft tissue when placed at the time of implant placement in patients with thin or deficient keratinized tissue (KT). The primary endpoint of the study was the change in thickness and height of the buccal KT. Secondary endpoints included stability of the midbuccal soft tissue level; clinician rating of color, texture, and contour of treatment site; probing pocket depths (PPDs); assessment of satisfaction outcome; and patient assessment of pain/discomfort. Thirty-two patients were enrolled and 31 patients completed the study. There were no statistically significant (SS) differences between the MG and control groups for height measures. There was no SS difference for KT thickness (P = .117) between the groups at the final measurement (3 months postsurgery). However, there was an SS difference (P = .009) in favor of the MG group when comparing the difference in presurgical KT thickness to that 3 months postsurgery. Thus, MG was successful (compared to the control) in increasing the buccal KT. There were no SS differences between the groups for any of the other endpoints, including color, texture, contour, and pain assessment at any visit or successful outcome between the treatment group and the control. More cases and longer follow-up of implants placed with MG are needed to verify the results of this randomized prospective study.

Pooled analyses integrate data from multiple studies and achieve a larger sample size for enhanced statistical power. When heterogeneity exists in variables' effects on the outcome across studies, the simple pooling strategy fails to present a fair and complete picture of the effects of heterogeneous variables. Thus, it is important to investigate the homogeneous and heterogeneous structure of variables in pooled studies. In this article, we consider the pooled cohort studies with time-to-event outcomes and propose a penalized Cox partial likelihood approach with adaptively weighted composite penalties on variables' homogeneous and heterogeneous effects. We show that our method can characterize the variables as having heterogeneous, homogeneous, or null effects, and estimate non-zero effects. The results are readily extended to high-dimensional applications where the number of parameters is larger than the sample size. The proposed selection and estimation procedure can be implemented using the iterative shooting algorithm. We conduct extensive numerical studies to evaluate the performance of our proposed method and demonstrate it using a pooled analysis of gene expression in patients with ovarian cancer.

BACKGROUND: Whether older adults with sarcopenia who underperform controls on tests of physical performance and cognition also have a higher likelihood of combined cognitive-physical impairment is not clear. We assessed the impact of sarcopenia on impairment in both aspects of functionality and the relative contribution of its components, muscle mass and strength. METHODS: Two hundred and twenty-three community-dwelling adults aged 40 years and older (mean age =68.1+/-10.6 years; 65% female) were recruited and underwent physical functionality, anthropometry, and cognitive testing. Participants with low muscle mass were categorized as pre-sarcopenic; those with low muscle mass and muscle strength as sarcopenic; those with higher muscle mass and low muscle strength only were categorized as non-sarcopenic and were compared on risk of cognitive impairment (Montreal Cognitive Assessment <26; Ascertaining Dementia 8 >/=2), physical impairment (Mini Physical Performance Test <12), both, or neither by ordinal logistic regression. RESULTS: Compared to controls, those with sarcopenia were six times more likely to have combined cognitive impairment/physical impairment with a fully adjusted model showing a three-fold increased odds ratio. The results were consistent across different measures of global cognition (odds ratio =3.46, 95% confidence interval =1.07-11.45 for the Montreal Cognitive Assessment; odds ratio =3.61, 95% confidence interval =1.11-11.72 for Ascertaining Dementia 8). Pre-sarcopenic participants were not different from controls. The effect of sarcopenia on cognition is related to low muscle strength rather than low muscle mass. CONCLUSION: Individuals with sarcopenia are not only more likely to have single but also to have dual impairment in cognitive and physical function. Interventions designed to prevent sarcopenia and improve muscle strength may help reduce the burden of cognitive and physical impairments of functionality in community-dwelling seniors.

ETS-related gene (ERG) is a transcription factor that has been linked to angiogenesis. Very little research has been done to assess ERG expression in central nervous system (CNS) tumors. We evaluated 57 CNS tumors, including glioblastomas (GBMs) and hemangioblastomas (HBs), as well as two arteriovenous malformations and four samples of normal brain tissue with immunohistochemistry using a specific ERG rabbit monoclonal antibody. In addition, immunostains for CD31, CD34, and alpha-smooth muscle actin (alpha-SMA) were performed on all samples. CD31 demonstrated variable and sometimes weak immunoreactivity for endothelial cells. Furthermore, in 1 case of a GBM, CD34 stained not only endothelial cells, but also tumor cells. In contrast, we observed that ERG was only expressed in the nuclei of endothelial cells, for example, in the hyperplastic vascular complexes that comprise the glomeruloid microvascular proliferation seen in GBMs. Conversely, alpha-SMA immunoreactivity was identified in the abluminal cells of these hyperplastic vessels. Quantitative evaluation with automated methodology and custom Matlab 2008b software was used to calculate percent staining of ERG in each case. We observed significantly higher quantitative expression of ERG in HBs than in other CNS tumors. Our results show that ERG is a novel, reliable, and specific marker for endothelial cells within CNS tumors that can be used to better study the process of neovascularization.

BACKGROUND: Epidemiologic data on genetic susceptibility to cardiovascular effects of arsenic exposure from drinking water are limited. OBJECTIVE: We investigated whether the association between well-water arsenic and cardiovascular disease (CVD) differed by 170 single nucleotide polymorphisms (SNPs) in 17 genes related to arsenic metabolism, oxidative stress, inflammation, and endothelial dysfunction. METHOD: We conducted a prospective case-cohort study nested in the Health Effects of Arsenic Longitudinal Study, with a random subcohort of 1,375 subjects and 447 incident fatal and nonfatal cases of CVD. Well-water arsenic was measured in 2000 at baseline. The CVD cases, 56 of which occurred in the subcohort, included 238 coronary heart disease cases, 165 stroke cases, and 44 deaths due to other CVD identified during follow-up from 2000 to 2012. RESULTS: Of the 170 SNPs tested, multiplicative interactions between well-water arsenic and two SNPs, rs281432 in ICAM1 (Padj = 0.0002) and rs3176867 in VCAM1 (Padj = 0.035), were significant for CVD after adjustment for multiple testing. Compared with those with GC or CC genotype in rs281432 and lower well-water arsenic, the adjusted hazard ratio (aHR) for CVD was 1.82 (95% CI: 1.31, 2.54) for a 1-SD increase in well-water arsenic combined with the GG genotype, which was greater than expected given aHRs of 1.08 and 0.96 for separate effects of arsenic and the genotype alone, respectively. Similarly, the joint aHR for arsenic and the rs3176867 CC genotype was 1.34 (95% CI: 0.95, 1.87), greater than expected given aHRs for their separate effects of 1.02 and 0.84, respectively. CONCLUSIONS: Associations between CVD and arsenic exposure may be modified by genetic variants related to endothelial dysfunction.

BACKGROUND: Substance use screening is widely encouraged in healthcare settings, but the lack of a screening approach that fits easily into clinical workflows has restricted its broad implementation. The Substance Use Brief Screen (SUBS) was developed as a brief, self-administered instrument to identify unhealthy use of tobacco, alcohol, illicit drugs, and prescription drugs. We evaluated the validity and test-retest reliability of the SUBS in adult primary care patients. METHODS: Adults age 18-65 were enrolled from urban safety net primary care clinics to self-administer the SUBS using touch-screen tablet computers for a test-retest reliability study (n=54) and a two-site validation study (n=586). In the test-retest reliability study, the SUBS was administered twice within a 2-week period. In the validation study, the SUBS was compared to reference standard measures, including self-reported measures and saliva drug tests. We measured test-retest reliability and diagnostic accuracy of the SUBS for detection of unhealthy use and substance use disorder for tobacco, alcohol, and drugs (illicit and prescription drug misuse). RESULTS: Test-retest reliability was good or excellent for each substance class. For detection of unhealthy use, the SUBS had sensitivity and specificity of 97.8% (95% CI 93.7 to 99.5) and 95.7% (95% CI 92.4 to 97.8), respectively, for tobacco; and 85.2% (95% CI 79.3 to 89.9) and 77.0% (95% CI 72.6 to 81.1) for alcohol. For unhealthy use of illicit or prescription drugs, sensitivity was 82.5% (95% CI 75.7 to 88.0) and specificity 91.1% (95% CI 87.9 to 93.6). With respect to identifying a substance use disorder, the SUBS had sensitivity and specificity of 100.0% (95% CI 92.7 to 100.0) and 72.1% (95% CI 67.1 to 76.8) for tobacco; 93.5% (95% CI 85.5 to 97.9) and 64.6% (95% CI 60.2 to 68.7) for alcohol; and 85.7% (95% CI 77.2 to 92.0) and 82.0% (95% CI 78.2 to 85.3) for drugs. Analyses of area under the receiver operating curve (AUC) indicated good discrimination (AUC 0.74-0.97) for all substance classes. Assistance in completing the SUBS was requested by 11% of participants. CONCLUSIONS: The SUBS was feasible for self-administration and generated valid results in a diverse primary care patient population. The 4-item SUBS can be recommended for primary care settings that are seeking to implement substance use screening.

BACKGROUND: Cannabis (marijuana) use and acceptance towards use are increasing in the US, and state-level policies are becoming more liberal. A wealth of research has been conducted to examine risk factors for use; however, studies rarely differentiate between different forms of marijuana. OBJECTIVE: We sought to determine prevalence of use and delineate who is at risk for use of hashish, a more potent form of marijuana. METHODS: We examined data from a nationally representative sample of high school seniors in the Monitoring the Future study (2007-2011; weighted n = 10 597). We determined how sociodemographic factors and reasons for marijuana use correlated with recent (12 month) hashish use. RESULTS: Prevalence of recent hashish use was 6.5% and it was used by 18.3% of recent marijuana users. Hashish and other marijuana use tended to share many of the same correlates; however, associations were often stronger for hashish use. Females were consistently at low risk for use and users of other drugs were consistently at high risk for use. Black students tended to be at low risk for hashish use. Low risk of identifying as Hispanic or religious and high risk of higher personal income or going out more evenings per week for fun disappeared when controlling for other drug use. Using marijuana because the student felt he/she was "hooked" nearly doubled the odds for hashish use. CONCLUSIONS: This was the first national study to examine prevalence and correlates of hashish use. These findings can inform prevention in a time of increasing popularity of marijuana use.

Policies supporting breastfeeding vary by state, but little is known about the geographical aspects of this variation. This study describes state breastfeeding licensing and administrative regulations targeting child care settings, compares regulations with national standards, and examines the spatial patterning and clustering of these regulations throughout the United States (US). We compared regulations for child care centers (centers) and family child care homes (homes) with national standards for: (1) general breastfeeding support; (2) designated place for breastfeeding; (3) no solids before infants are four months of age; and (4) no formula for breastfed infants without parent permission. We scored state regulations as 0 = standard not addressed, 1 = standard partially addressed, and 2 = standard fully addressed. We considered each regulation individually, and also summed scores to provide an overall rating of regulations by state. We mapped regulations using geographic information systems technology, and explored overall and local spatial autocorrelation using global and local variants of Moran's I. Five states had regulations for centers and two for homes that addressed all four standards. Mean regulation scores were 0.35, 0.20, 0.98, 0.74 for centers, and 0.17, 0.15, 0.79, 0.58 for homes. Local Moran's I revealed that New York and Pennsylvania had substantially stronger regulations than their adjacent states, while Florida had weaker regulations than its neighbors. Overall, few states had regulations that met breastfeeding standards. We identified some patterns of spatial correlation, suggesting avenues for future research to better understand distributions of regulations across the US.