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1.  More than Memory Impairment in Voltage-Gated Potassium Channel Complex Encephalopathy 
Autoimmune encephalopathies (AE) are a heterogeneous group of neurological disorders that affect cognition. Although memory difficulties are commonly endorsed, few reports of AE inclusively assess all cognitive domains in detail. Our aim was to perform an unbiased cognitive evaluation of AE patients with voltage-gated potassium channel complex antibodies (VGKCC-Abs) in order to delineate cognitive strengths and weaknesses.
We assessed serial VGKCC-Abs AE subjects (n=12) with a comprehensive evaluation of memory, executive functions, visuospatial skills, and language. Clinical MRI (n=10/12) was evaluated. Five subjects had serial cognitive testing available, permitting descriptive analysis of change.
Subjects demonstrated mild to moderate impairment in memory (mean Z=−1.9) and executive functions (mean Z=−1.5), with variable impairments in language and sparing of visuospatial skills. MRI findings showed T2 hyperintensities in medial temporal lobe (10/10) and basal ganglia (2/10). Serial cognitive examination revealed heterogeneity in cognitive function; whereas most patients improved in one or more domains, residual impairments were observed in some patients.
This study augments prior neuropsychological analyses in VGKCC-Ab AE by identifying not only memory and executive function deficits, but also language impairments, with preservation of visuospatial functioning. This study further highlights the importance of domain-specific testing to parse out the complex cognitive phenotypes of VGKCC-Ab AE.
PMCID: PMC4162838  PMID: 24981998
autoimmune; cognitive; LGI1
2.  Comparing CSF biomarkers and brain MRI in the diagnosis of sporadic Creutzfeldt-Jakob disease 
Neurology: Clinical Practice  2015;5(2):116-125.
We assessed the diagnostic utility of 3 CSF biomarkers—14-3-3 protein, total tau (T-tau), and neuron-specific enolase (NSE)—from the same lumbar puncture to distinguish between participants with neuropathologically confirmed sporadic Creutzfeldt-Jakob disease (sCJD, n = 57) and controls with nonprion rapidly progressive dementia (npRPD, n = 41). Measures of diagnostic accuracy, sensitivity, specificity, positive predictive value, and negative predictive value, as well as logistic regression and area under the receiver operator curve (AUC), were used to assess the ability of these CSF biomarkers, alone or concomitantly, to predict diagnosis. In a subcohort with available MRI (sCJD n = 57, npRPD = 32), we compared visual assessment of diffusion-weighted imaging MRI sequences to these CSF biomarkers. MRI was the best predictor, with an AUC of 0.97 (confidence interval [CI] 0.92–1.00) and a diagnostic accuracy of 97% (CI 90%–100%). Of the CSF biomarkers, T-tau had a higher diagnostic accuracy (79.6%) than 14-3-3 (70.4%, CI for difference 8.7%, 9.7%; p = 0.048) or NSE (71.4%, CI for difference 7.6%, 8.7%; p = 0.03).
PMCID: PMC4404282  PMID: 26137420
3.  Side of Cancer Does Not Influence Limb Volumes in Women Prior to Breast Cancer Surgery 
Lymphatic Research and Biology  2014;12(3):189-193.
Background: Understanding normal volume asymmetry is essential for accurate assessment of limb volume changes following breast cancer (BC) treatment in which lymphatic function is disrupted. The purposes of this study were to evaluate for differences in dominant and nondominant limb volumes and to evaluate for interactions between the effects of dominance and side of cancer on limb volume.
Methods and Results: This study evaluated preoperative limb volumes of 397 women enrolled in a prospective, longitudinal study of neuropathic pain and lymphedema. Volume was calculated from circumference. Limb resistance was measured with bioimpedance. Women were dichotomized into two groups: those whose cancer was on their dominant side and those whose cancer was on their nondominant side. Analyses of variance were used to evaluate for differences. In 47%, BC occurred on the side of the dominant limb. Except for the 30 to 40 centimeter (cm) limb volume segment, a main effect of dominance was found for all measures. The volume of the dominant limb was significantly greater than that of the nondominant limb. No main effects were found for side of cancer. A statistically significant interaction was found only at the 0 to 10 cm limb volume segment.
Conclusions: Prior to BC treatment, the dominant limb demonstrated lower bioimpedance resistance (−2.09%) and greater total limb volume (1.12%) than the nondominant limb. Segmental volume differences were greatest at the proximal forearm segment (2.31%) and least at the proximal arm segment (0.21%). This study provides evidence that preoperative volume assessment is important due to normal variability associated with limb dominance.
PMCID: PMC4171111  PMID: 24834791
4.  Decision Rightness and Emotional Responses to Abortion in the United States: A Longitudinal Study 
PLoS ONE  2015;10(7):e0128832.
Arguments that abortion causes women emotional harm are used to regulate abortion, particularly later procedures, in the United States. However, existing research is inconclusive. We examined women’s emotions and reports of whether the abortion decision was the right one for them over the three years after having an induced abortion.
We recruited a cohort of women seeking abortions between 2008-2010 at 30 facilities across the United States, selected based on having the latest gestational age limit within 150 miles. Two groups of women (n=667) were followed prospectively for three years: women having first-trimester procedures and women terminating pregnancies within two weeks under facilities’ gestational age limits at the same facilities. Participants completed semiannual phone surveys to assess whether they felt that having the abortion was the right decision for them; negative emotions (regret, anger, guilt, sadness) about the abortion; and positive emotions (relief, happiness). Multivariable mixed-effects models were used to examine changes in each outcome over time, to compare the two groups, and to identify associated factors.
The predicted probability of reporting that abortion was the right decision was over 99% at all time points over three years. Women with more planned pregnancies and who had more difficulty deciding to terminate the pregnancy had lower odds of reporting the abortion was the right decision (aOR=0.71 [0.60, 0.85] and 0.46 [0.36, 0.64], respectively). Both negative and positive emotions declined over time, with no differences between women having procedures near gestational age limits versus first-trimester abortions. Higher perceived community abortion stigma and lower social support were associated with more negative emotions (b=0.45 [0.31, 0.58] and b=-0.61 [-0.93, -0.29], respectively).
Women experienced decreasing emotional intensity over time, and the overwhelming majority of women felt that termination was the right decision for them over three years. Emotional support may be beneficial for women having abortions who report intended pregnancies or difficulty deciding.
PMCID: PMC4496083  PMID: 26154386
5.  The Impact of Neighborhood Socioeconomic Position on Prevalence of Diabetes and Pre-diabetes in Older Latinos: The Sacramento Area Latino Study on Aging 
Diabetes is a leading cause of morbidity and mortality in Latinos, but few studies of disease risk in this subpopulation examine both area-level socioeconomic position and its association with individual-level risk factors. This study sought to examine the cross-sectional relationship between neighborhood socioeconomic position (NSEP) and prevalent diabetes and pre-diabetes status among older Latinos. Longitudinal health data were collected from 1,789 participants in the Sacramento Area Latino Study on Aging (SALSA). Among SALSA participants, higher NSEP was associated with lower diabetes prevalence (p = 0.001). Adjustment for BMI and other individual-level factors did not affect this relationship. No association was observed between NSEP and pre-diabetes in both unadjusted and adjusted models. Neighborhoods with higher SEP had a lower prevalence of diabetes. This study highlights the importance of considering neighborhood factors that may place older Latinos at high risk for this disease.
PMCID: PMC4470296  PMID: 26078026
neighborhood; diabetes; Latinos; aging
Investigators often gather longitudinal data to assess changes in responses over time within subjects and to relate these changes to within-subject changes in predictors. Missing data are common in such studies and predictors can be correlated with subject-specific effects. Maximum likelihood methods for generalized linear mixed models provide consistent estimates when the data are `missing at random' (MAR) but can produce inconsistent estimates in settings where the random effects are correlated with one of the predictors. On the other hand, conditional maximum likelihood methods (and closely related maximum likelihood methods that partition covariates into between- and within-cluster components) provide consistent estimation when random effects are correlated with predictors but can produce inconsistent covariate effect estimates when data are MAR. Using theory, simulation studies, and fits to example data this paper shows that decomposition methods using complete covariate information produce consistent estimates. In some practical cases these methods, that ostensibly require complete covariate information, actually only involve the observed covariates. These results offer an easy-to-use approach to simultaneously protect against bias from both cluster-level confounding and MAR missingness in assessments of change.
PMCID: PMC4456042  PMID: 26052246
bias; conditional likelihood; confounding; consistent estimation
7.  Metacognition in the behavioral variant of frontotemporal dementia and Alzheimer’s disease 
Neuropsychology  2014;28(3):436-447.
Impaired self-awareness is characteristic of nearly all dementias, including Alzheimer’s disease (AD), but the deficit is most severe in the behavioral variant of frontotemporal dementia (bvFTD). The prominence of frontal pathology in bvFTD suggests that failure of online monitoring, the process by which individuals monitor their own cognitive processing in real time, is an important contributor. Metacognitive research offers several approaches to measure self-assessment, some more and others less sensitive to online monitoring. The goal of this study was to assess metacognition in bvFTD using several approaches, and compare the results with those in AD.
We examined metacognition in 12 patients with bvFTD, 14 with AD and 35 healthy controls using Feeling of Knowing (FOK), Ease of Learning (EOL), Judgment of Learning (JOL), and Retrospective Confidence Rating (CR) tasks, as well as response to feedback about performance.
BvFTD and AD were both impaired at FOK compared with controls, although AD showed some sparing. Both groups were similarly impaired at CR and neither group was impaired at JOL after accounting for memory performance. Most strikingly, bvFTD patients failed to appropriately adjust their predictions about future memory performance even after receiving explicit feedback that they had performed worse than they expected.
Both bvFTD and AD show deficits in online monitoring, although the deficit appears more severe in bvFTD. The insensitivity of bvFTD patients to overt feedback may point to unique mechanisms, possibly frontally mediated, that add to their severe lack of self-awareness.
PMCID: PMC4085356  PMID: 24548124
Feeling of knowing; Judgment of Learning; Metamemory; Dementia; Frontal lobe
8.  Cytokine Candidate Genes Predict the Development of Secondary Lymphedema Following Breast Cancer Surgery 
Lymphatic Research and Biology  2014;12(1):10-22.
Background: Lymphedema (LE) is a frequent complication following breast cancer treatment. While progress is being made in the identification of phenotypic risk factors for the development of LE, little information is available on the molecular characterization of LE. The purpose of this study was to determine if variations in pro- and anti-inflammatory cytokine genes were associated with LE following breast cancer treatment.
Methods and Results: Breast cancer patients completed a number of self-report questionnaires. LE was evaluated using bioimpedance spectroscopy. Genotyping was done using a custom genotyping array. No differences were found between patients with (n=155) and without LE (n=387) for the majority of the demographic and clinical characteristics. Patients with LE had a significantly higher body mass index, more advanced disease, and a higher number of lymph nodes removed. Genetic associations were identified for three genes (i.e., interleukin (IL4) 4 (rs2227284), IL 10 (rs1518111), and nuclear kappa factor beta 2 (NFKB2 (rs1056890)) associated with inflammatory responses.
Conclusions: These genetic associations suggest a role for a number of pro- and anti-inflammatory genes in the development of LE following breast cancer treatment.
PMCID: PMC3961780  PMID: 24502445
Journal of neurogenetics  2014;28(0):122-135.
Preoperative breast pain in women with breast cancer may result from a number of causes. Previous work from our team found that breast pain occurred in 28.2% of women (n=398) who were about to undergo breast cancer surgery. The occurrence of preoperative breast pain was associated with a number of demographic and clinical characteristics, as well as variation in two cytokine genes. Given that ion channels regulate excitability of sensory neurons, we hypothesized that variations in potassium channel genes would be associated with preoperative breast pain in these patients. Therefore, in this study we evaluated for associations between single nucleotide polymorphisms and inferred haplotypes among 10 potassium channel genes and the occurrence of preoperative breast pain in patients scheduled to undergo breast cancer surgery. Multivariable logistic regression analyses were used to identify those genetic variations that were associated with the occurrence of preoperative breast pain while controlling for age and genomic estimates of and self-reported race/ethnicity. Variations in four potassium channel genes: 1) potassium voltage-gated channel, delayed rectifier, subfamily S, member 1 (KCNS1); 2) potassium inwardly-rectifying channel, subfamily J, member 3 (KCNJ3); 3) KCNJ6; and 4) potassium channel, subfamily K, member 9 (KCNK9) were associated with the occurrence of breast pain. Findings from this study warrant replication in an independent sample of women who report breast pain following one or more breast biopsies.
PMCID: PMC4035357  PMID: 24392765
breast pain; preoperative pain; potassium channel genes; breast cancer; candidate genes
10.  Longitudinal gray matter contraction in three variants of primary progressive aphasia: A tenser-based morphometry study 
NeuroImage : Clinical  2015;8:345-355.
The present study investigated the pattern of longitudinal changes in cognition and anatomy in three variants of primary progressive aphasia (PPA). Eight patients with the non-fluent variant of PPA (nfvPPA), 13 patients with the semantic variant (svPPA), seven patients with the logopenic variant (lvPPA), and 29 age-matched, neurologically healthy controls were included in the study. All participants underwent longitudinal MRI, neuropsychological and language testing at baseline and at a 1-year follow-up. Tenser-based morphometry (TBM) was applied to T1-weighted MRI images in order to map the progression of gray and white matter atrophy over a 1-year period. Results showed that each patient group was characterized by a specific pattern of cognitive and anatomical changes. Specifically, nfvPPA patients showed gray matter atrophy progression in the left frontal and subcortical areas as well as a decline in motor speech and executive functions; svPPA patients presented atrophy progression in the medial and lateral temporal lobe and decline in semantic memory abilities; and lvPPA patients showed atrophy progression in lateral/posterior temporal and medial parietal regions with a decline in memory, sentence repetition and calculations. In addition, in all three variants, the white matter fibers underlying the abovementioned cortical areas underwent significant volume contraction over a 1-year period.
Overall, these results indicate that the three PPA variants present distinct patterns of neuroanatomical contraction, which reflect their clinical and cognitive progression.
•PPA variants present distinct patterns of neuroanatomical contraction.•Non-fluent variant of PPA shows GM contraction in left frontal and subcortical areas.•Semantic variant of PPA shows GM contraction in medial and lateral temporal lobe.•Logopenic variant of PPA shows GM contraction in lateral/posterior temporal and medial parietal regions.
PMCID: PMC4473099  PMID: 26106560
11.  Quinacrine treatment trial for sporadic Creutzfeldt-Jakob disease 
Neurology  2013;81(23):2015-2023.
To determine whether oral quinacrine increases survival in sporadic Creutzfeldt-Jakob disease (sCJD).
This NIH/National Institute on Aging–funded, double-blinded, placebo-controlled, stratified randomization treatment trial was conducted at the University of California, San Francisco from February 2005 through May 2009 (, NCT00183092). Subjects were randomized (50:50) to quinacrine (300 mg daily) or placebo with inpatient evaluations at baseline, and planned for months 2, 6, and 12. Subjects returning for their month-2 visit were offered open-label quinacrine. The primary outcome was survival from randomization to month 2.
Of 425 patients referred, 69 subjects enrolled, 54 subjects were randomized to active drug or placebo, and 51 subjects with sCJD were included in survival analyses. Survival for the randomized portion of the trial (first 2 months) showed no significant difference between the 2 groups (log-rank statistic, p = 0.43; Cox proportional relative hazard = 1.43, quinacrine compared with placebo, 95% confidence interval = 0.58, 3.53). The quinacrine-treated group, however, declined less on 2 of 3 functional scales, the modified Rankin and Clinical Dementia Rating, than the placebo group during the first 2 months.
This interventional study provides Class I evidence that oral quinacrine at 300 mg per day does not improve 2-month survival of patients with sCJD, compared with placebo. Importantly, this study shows that double-blinded, placebo-controlled, randomized treatment trials are possible in prion disease. Furthermore, the quantitative data collected on the course of sCJD will be useful for future trials.
Classification of evidence:
This study provides Class I evidence that quinacrine does not improve survival for people with sCJD when given orally at a dose of 300 mg per day for 2 months.
PMCID: PMC4211922  PMID: 24122181
12.  Impact of Gender and Blood Pressure on Post-Stroke Cognitive Decline among Older Latinos 
Post-stroke cognitive decline (PSCD) is an important consequence of stroke that may be more severe in women than men. The existence of any gender differences in PSCD among Mexican Americans, and their potential mechanisms, such as blood pressure (BP), remain unknown. We assessed PSCD stratified on gender in older Mexican Americans and explored the influence of pre-stroke and post-stroke systolic BP on PSCD.
Among 1,576 non-demented, stroke-free adults 60 years or older when recruited in 1998–99 in the Sacramento Area Latino Study on Aging (SALSA) cohort, we examined pre-stroke and post-stroke longitudinal changes in Spanish English Verbal Learning test scores (WL), a verbal memory test, and errors on the Modified Mini Mental State Exam (3MSE) scores, a global cognition test, stratified by gender, adjusting for baseline and time-varying covariates with linear mixed-effects models.
We identified 151 adults (mean age, 72 ± 8 years) with incident first-ever stroke during ten years of follow-up. After adjustment for age, education and time-varying depressive symptoms, 3MSE errors increased by 22%/year (95% CI, 6.8%–36.7%) in men and 13.2%/year (95% CI, 3.5%–22.9%) in women over the post-stroke period. Post-stroke WL scores improved by 0.05 words/year (95% CI, −0.24–0.33) in men and by 0.09 words/year (95% CI, −0.16–0.34) in women. Results persisted after adjustment for time-varying systolic BP.
Among this population of older Mexican Americans, PSCD did not differ by gender. We found no evidence that systolic BP influenced PSCD in women or men.
PMCID: PMC4030756  PMID: 22748715
[MeSH] Cerebrovascular disease/stroke; Cognition; Hispanic Americans; Sex; Epidemiology
13.  Interleukin-6, Age, and Corpus Callosum Integrity 
PLoS ONE  2014;9(9):e106521.
The contribution of inflammation to deleterious aging outcomes is increasingly recognized; however, little is known about the complex relationship between interleukin-6 (IL-6) and brain structure, or how this association might change with increasing age. We examined the association between IL-6, white matter integrity, and cognition in 151 community dwelling older adults, and tested whether age moderated these associations. Blood levels of IL-6 and vascular risk (e.g., homocysteine), as well as health history information, were collected. Processing speed assessments were administered to assess cognitive functioning, and we employed tract-based spatial statistics to examine whole brain white matter and regions of interest. Given the association between inflammation, vascular risk, and corpus callosum (CC) integrity, fractional anisotropy (FA) of the genu, body, and splenium represented our primary dependent variables. Whole brain analysis revealed an inverse association between IL-6 and CC fractional anisotropy. Subsequent ROI linear regression and ridge regression analyses indicated that the magnitude of this effect increased with age; thus, older individuals with higher IL-6 levels displayed lower white matter integrity. Finally, higher IL-6 levels were related to worse processing speed; this association was moderated by age, and was not fully accounted for by CC volume. This study highlights that at older ages, the association between higher IL-6 levels and lower white matter integrity is more pronounced; furthermore, it underscores the important, albeit burgeoning role of inflammatory processes in cognitive aging trajectories.
PMCID: PMC4154691  PMID: 25188448
14.  Type 2 Diabetes and 10-Year Risk of Dementia and Cognitive Impairment Among Older Mexican Americans 
Diabetes Care  2013;36(9):2600-2606.
Type 2 diabetes has been linked with increased risk of dementia and cognitive impairment among older adults and with premature mortality in young and middle-aged adults. No studies have evaluated the association between diabetes and dementia among Mexican Americans, a population with a high burden of diabetes. We evaluated the association of diabetes with incidence of dementia and cognitive impairment without dementia (CIND) among older Mexican Americans while accounting for competing risk from death.
This study included 1,617 participants 60–98 years of age from the Sacramento Area Latino Study on Aging followed up to 10 years from 1998. We evaluated the association between diabetes and dementia/CIND with competing risk regression models.
Participants free of dementia/CIND at baseline (n = 1,617) were followed annually up to 10 years. There were 677 (41.9%) participants with diabetes, 159 (9.8%) incident dementia/CIND cases, and 361 (22.3%) deaths. Treated and untreated diabetes (hazard ratio 2.12 [95% CI 1.65–2.73] and 2.15 [1.58–2.95]) and dementia/CIND (2.48 [1.75–3.51]) were associated with an increased risk of death. In models adjusted for competing risk of death, those with treated and untreated diabetes had an increased risk of dementia/CIND (2.05 [1.41–2.97] and 1.55 [0.93–2.58]) compared with those without diabetes.
These findings provide evidence that the association between type 2 diabetes and dementia/CIND among Mexican Americans remains strong after accounting for competing risk of mortality. Treatments that modify risk of death among those with diabetes may change future dementia risk.
PMCID: PMC3747945  PMID: 23514732
15.  Big 5 Personality changes in Greek bvFTD, AD, and MCI patients 
Patients with neurodegenerative disease show distinct patterns of personality change, some of which may be traced to focal neurologic damage, while others may be mediated by cultural reactions to functional impairment. While such changes are early and pervasive in behavioral variant frontotemporal dementia (bvFTD), and milder changes are seen in Alzheimer’s (AD), no study has examined all Big 5 factors of personality in mild cognitive impairment (MCI) patients. Also, the influence of culture and ethnicity on disease-related personality changes has seldom been examined. Premorbid and current personality were measured in 47 Greek patients with bvFTD, AD, and MCI according to informant reports using the TPQue5, a 5-factor inventory in the Greek language and accounting for Greek cultural factors. bvFTDs showed greater decreases in conscientiousness than ADs and MCIs. ADs and MCIs showed increased neuroticism, while the bvFTD patients were rated as having become much less neurotic in the course of their disease. The pattern of personality change in MCIs was very similar to that of ADs, supporting recent evidence that personality changes occur as early as the MCI disease stage. In all groups, personality changes were similar to those previously described in non-Mediterranean cultures, supporting the hypothesis that they may result directly from disease-specific neurologic processes.
PMCID: PMC3553233  PMID: 23060360
personality; frontotemporal dementia; Alzheimer’s disease; mild cognitive impairment; Big Five
Hypertension  2013;63(1):181-187.
Reduced Heart Rate Variability is a strong predictor of cardiovascular risk factors, cardiovascular events and mortality; and thus may be associated with cognitive neurodegeneration. Yet this has been relatively unexplored, particularly in minority populations with high cardiovascular burden. We used data from the Sacramento Area Latino Study on Aging to examine the cross-sectional association of reduced heart rate variability with cognitive function among elderly Mexican Americans. A total of 869 participants (mean age of 75 years; 59% females) had their 6-minute heart rate variability measured using an ECG monitor and respiration pacer in response to deep breathing. We used the Mean Circular Resultant, known as R bar, as a measure of heart rate variability and categorized it into quartiles (Q1 to Q4 of R bar: reduced to high heart rate variability). Cognitive function was assessed using the Modified Mini Mental State Exam, a 100-point test of global cognitive function and the Spanish and English Verbal Learning Test, a 15-point test of verbal memory recall. In fully-adjusted linear regression models, participants in quartile 1 had a 4-point lower Modified Mini Mental State Exam score (p<0.01), those in quartile 2 had 2-point lower score (p=0.04), and those in quartile 3 had 1-point lower score (p=0.35), as compared to those in the highest quartile of R bar. Reduced R bar was not associated with verbal memory. Our results suggest that reduced heart rate variability is associated with worse performance on the test of global cognitive function, above and beyond traditional cardiovascular risk factors.
PMCID: PMC4045649  PMID: 24144650
Aging; autonomic function; cognition; epidemiology; heart rate variability
17.  Differences in Sleep Disturbance, Fatigue and Energy Levels Between Women With and Without Breast Pain Prior to Breast Cancer Surgery 
Breast (Edinburgh, Scotland)  2012;22(3):273-276.
The purpose of this study was to evaluate for differences in occurrence and severity ratings of sleep disturbance, fatigue, and decreased energy in women who reported breast pain prior to surgery for breast cancer. Of the 390 women who completed self-report measures for each symptom, 28.2% reported pain in their breast prior to surgery. A higher percentage of women in the pain group (i.e., 66.7% versus 53.5%) reported clinically meaningful levels of sleep disturbance. However, no between group differences were found in the severity of sleep disturbance, fatigue, or decreased energy. Findings from this study suggest that sleep disturbance, fatigue, and decreased levels of energy are significant problems for women prior to breast cancer surgery. Future studies need to evaluate for specific characteristics that place women at greater risk for these symptoms as well as the mechanisms that underlie these symptoms.
PMCID: PMC3524341  PMID: 22858121
pain; fatigue; energy; sleep disturbance; breast cancer; surgery
18.  Clinical features and outcomes in patients with secondary Ewing sarcoma 
Pediatric blood & cancer  2012;60(4):611-615.
Ewing sarcoma (EWS) is rarely diagnosed as a second malignancy. We sought to describe a cohort of patients with secondary EWS and investigate if patient characteristics and survival differ between patients with secondary and primary EWS.
Patients with EWS or peripheral primitive neuroectodermal tumor (PNET) reported to the SEER database from 1973 to 2008 were evaluated based on primary or secondary tumor sequence. Overall survival was estimated by Kaplan-Meier methods and evaluated using the log-rank test. Competing risk analysis was used to describe risk of death due to malignancy rather than other causes.
58 cases of secondary EWS were reported, accounting for 2.1% of all EWS cases. The median latency from primary malignancy to secondary EWS was 64 months (range 1–282 months). 12.1% of patients with secondary EWS received radiation to the site of secondary tumor during therapy for their primary malignancy. Patients with secondary EWS were more likely to have axial tumors (77.4% vs. 62.5%; p = 0.03) and smaller tumors (75.0% vs. 48.2% < 8 cm; p = 0.001). Five-year overall survival from diagnosis was inferior for patients with secondary compared to primary EWS (34.3% vs. 52.2%; p = 0.002). However, patients with secondary tumors were less likely than those with primary EWS to die from their malignancy (hazard ratio 0.44; 95% CI 0.23–0.85).
Secondary EWS accounts for a minority of cases of EWS. Tumor size and site and patient survival differ among patients with primary and secondary EWS.
PMCID: PMC3488141  PMID: 22847990
19.  Differences in Depression, Anxiety, and Quality of Life Between Women with and without Breast Pain Prior to Breast Cancer Surgery 
Purpose of the research
Little is known about the relationships between pain, anxiety, and depression in women prior to breast cancer surgery. The purpose of this study was to evaluate for differences in anxiety, depression, and quality of life (QOL) in women who did and did not report the occurrence of breast pain prior to breast cancer surgery. We hypothesized that women with pain would report higher levels of anxiety and depression as well as poorer QOL than women without pain.
Methods and sample
A total of 390 women completed self-report measures of pain, anxiety depression, and QOL prior to surgery.
Key Results
Women with preoperative breast pain (28%) were significantly younger, had a lower functional status score, were more likely to be Non-white and to have gone through menopause. Over 37% of the sample reported clinically meaningful levels of depressive symptoms. Almost 70% of the sample reported clinically meaningful levels of anxiety. Patients with preoperative breast pain reported significantly higher depression scores and significantly lower physical well-being scores. No between group differences were found for patients' ratings of state and trait anxiety or total QOL scores.
Findings from this study suggest that, regardless of pain status, anxiety and depression are common problems in women prior to breast cancer surgery.
PMCID: PMC3524405  PMID: 22892272
breast pain; breast cancer surgery; anxiety; depression; quality of life; psychological distress
20.  Likelihood-based analysis of longitudinal data from outcome-related sampling designs 
Biometrics  2013;70(1):44-52.
Investigators commonly gather longitudinal data to assess changes in responses over time and to relate these changes to within-subject changes in predictors. With rare or expensive outcomes such as uncommon diseases and costly radiologic measurements, outcome-dependent, and more generally outcome-related, sampling plans can improve estimation efficiency and reduce cost. Longitudinal follow up of subjects gathered in an initial outcome-related sample can then be used to study the trajectories of responses over time and to assess the association of changes in predictors within subjects with change in response. In this paper we develop two likelihood-based approaches for fitting generalized linear mixed models (GLMMs) to longitudinal data from a wide variety of outcome-related sampling designs. The first is an extension of the semi-parametric maximum likelihood approach developed in and applies quite generally. The second approach is an adaptation of standard conditional likelihood methods and is limited to random intercept models with a canonical link. Data from a study of Attention Deficit Hyperactivity Disorder in children motivates the work and illustrates the findings.
PMCID: PMC3954410  PMID: 24571396
Conditional likelihood; Retrospective sampling; Subject-specific models
21.  Characteristics and Outcomes of Patients with Ewing Sarcoma Over 40 Years of Age at Diagnosis 
Cancer epidemiology  2012;37(1):29-33.
The peak incidence of Ewing sarcoma (EWS) is in adolescence, with little known about patients who are ≥ 40 years at diagnosis. We describe the clinical characteristics and survival of this rare group.
This retrospective cohort study utilized the Surveillance Epidemiology and End Results database. 2780 patients were identified; including 383 patients diagnosed ≥ 40 years. Patient characteristics between age groups were compared using chi-squared tests. Survival from diagnosis to death was estimated via Kaplan-Meier methods, compared with log-rank tests, and modeled using multivariable Cox methods. A competing risks analysis was performed to evaluate death due to cancer.
Patients ≥ 40 years of age were more likely to have extra-skeletal tumors (66.1% v 31.7%; p<0.001), axial tumors (64.0% v 57.2%; p=0.01), and metastatic disease at diagnosis (35.5% v 30.0%; p=0.04) compared to younger patients. Five-year survival for those age ≥ 40 and age < 40 were 40.6% and 54.3%, respectively (p<0.0001). A Cox multivariable model controlling for differences between groups confirmed inferior survival for older patients (hazard ratio for death of 2.04; 95% CI 1.63 - 2.54; p < 0.0001); though treatment data were unavailable and not controlled for in the model. A competing risks analysis confirmed increased risk of cancer-related death in older patients.
Patients ≥ 40 years at diagnosis with EWS are more likely to have extra-skeletal tumors, metastatic disease, and axial primary tumors suggesting a difference in tumor biology. Independent of differences in these characteristics, older patients also have a lower survival rate.
PMCID: PMC3543501  PMID: 22959474
Ewing sarcoma; pediatric cancers; adult; age; SEER
22.  Prenatal Adversities and Latino Children’s Autonomic Nervous System Reactivity Trajectories from 6 Months to 5 Years of Age 
PLoS ONE  2014;9(1):e86283.
The purpose of the study was to determine whether mothers’ adversities experienced during early pregnancy are associated with offspring’s autonomic nervous system (ANS) reactivity trajectories from 6 months to 5 years of age. This cohort study of primarily Latino families included maternal interviews at 13–14 weeks gestation about their experience of a range of adversities: father’s absence, general social support, poverty level, and household density. ANS measures of heart rate, respiratory sinus arrhythmia (parasympathetic nervous system) and preejection period (sympathetic nervous system) were collected during resting and challenging conditions on children at 6 months and 1, 3.5 and 5 years of age. Reactivity measures were calculated as the mean of the responses to challenging conditions minus a resting condition. Fixed effects models were conducted for the 212 children with two or more timepoints of ANS measures. Interactions between maternal prenatal adversity levels and child age at time of ANS protocol were included in the models, allowing the calculation of separate trajectories or slopes for each level of adversity. Results showed no significant relations between mothers’ prenatal socioeconomic or social support adversity and offspring’s parasympathetic nervous system trajectories, but there was a statistically significant relationship between social support adversity and offspring’s heart rate trajectories (p<.05) and a borderline significant relationship between socioeconomic adversity and offspring’s sympathetic nervous system trajectories (p = .05). Children whose mothers experienced one, not two, social support adversity had the smallest increases in heart rate reactivity compared to children whose mothers experienced no adversity. The children whose mothers experienced no social support and no socioeconomic adversity had the largest increases in heart rate and preejection period respectively from 6 months to 5 years showing the most plasticity. Mothers’ prenatal adverse experiences may program their children’s physiologic trajectory to dampen their heart rate or sympathetic responsivity to challenging conditions.
PMCID: PMC3897676  PMID: 24466003
23.  Association of Chronic Kidney Disease Detected by Creatinine and Cystatin C with Death and Cardiovascular Events among Elderly Mexican-Americans: The Sacramento Area Latino Study on Aging (SALSA) 
Chronic kidney disease (CKD) is diagnosed by serum creatinine, which is biased by muscle mass, age and race. We evaluated whether cystatin C, an alternative measure of kidney function, can detect high risk CKD among elderly Mexican-Americans.
Sacramento Area Study of Latinos (SALSA)
1,435 Mexican-Americans ages 60–101 with mean follow-up 6.8 years
We estimated glomerular filtration rate (eGFR, ml/min/1.73m2)by creatinine and cystatin C, and classified persons into four mutually exclusive categories: (1) CKD neither (eGFRcreat ≥60 and eGFRcys ≥60); (2) CKD creatinine only (eGFRcreat <60 but eGFRcys ≥60); (3) CKD cystatin only (eGFRcreat ≥60 but eGFRcys <60); and (4) CKD both (eGFRcreat <60 and eGFRcys <60). We studied the association of each CKD classification with all-cause death and cardiovascular (CVD) death using Cox regression.
At baseline, mean was age 71±7; 34% (N=481) were diabetic and 68% (N=980) hypertensive. Compared with persons with no CKD by either marker, persons with CKD both had the highest risks for death (HR 2.30, 1.78–2.98) and CVD death (HR 2.75, 1.96–3.86) after full adjustment. Persons with CKD by cystatin C only were also at increased risk for death, HR 1.91 (1.37–2.67) and for CVD death, HR 2.56 (1.64–3.99)) compared to no CKD. In contrast, persons with CKD by creatinine only were not at increased risk for CVD death (HR 1.39, 0.71–2.72), but remained at higher risk for all-cause death (HR 1.95, 1.27–2.98).
Cystatin C may be a useful alternative in addition to creatinine to detect high risk CKD in elderly Mexican Americans.
PMCID: PMC3545054  PMID: 23252993
chronic kidney disease; Mexican-Americans; elderly; creatinine; cystatin C; cardiovascular disease
Study purposes were to determine the prevalence of persistent pain in the breast; characterize distinct persistent pain classes using growth mixture modeling, and evaluate for differences among these pain classes in demographic, preoperative, intraoperative, and postoperative characteristics. In addition, differences in the severity of common symptoms and quality of life outcomes measured prior to surgery, among the pain classes, were evaluated. Patients (n=398) were recruited prior to surgery and followed for six months. Using growth mixture modeling, patients were classified into no (31.7%), mild (43.4%), moderate (13.3%), and severe (11.6%) pain groups based on ratings of worst breast pain. Differences in a number of demographic, preoperative, intraoperative, and postoperative characteristics differentiated among the pain classes. In addition, patients in the moderate and severe pain classes reported higher preoperative levels of depression, anxiety, and sleep disturbance than the no pain class. Findings suggest that approximately 25% of women experience significant and persistent levels of breast pain in the first six months following breast cancer surgery.
PMCID: PMC3511823  PMID: 23182226
breast pain; persistent postsurgical pain; risk factors; breast cancer surgery; growth mixture modeling; latent class analysis
25.  Body Mass and White Matter Integrity: The Influence of Vascular and Inflammatory Markers 
PLoS ONE  2013;8(10):e77741.
High adiposity is deleteriously associated with brain health, and may disproportionately affect white matter integrity; however, limited information exists regarding the mechanisms underlying the association between body mass (BMI) and white matter integrity. The present study evaluated whether vascular and inflammatory markers influence the relationship between BMI and white matter in healthy aging. We conducted a cross-sectional evaluation of white matter integrity, BMI, and vascular/inflammatory factors in a cohort of 138 healthy older adults (mean age: 71.3 years). Participants underwent diffusion tensor imaging, provided blood samples, and participated in a health evaluation. Vascular risk factors and vascular/inflammatory blood markers were assessed. The primary outcome measure was fractional anisotropy (FA) of the genu, body, and splenium (corpus callosum); exploratory measures included additional white matter regions, based on significant associations with BMI. Regression analyses indicated that higher BMI was associated with lower FA in the corpus callosum, cingulate, and fornix (p<.001). Vascular and inflammatory factors influenced the association between BMI and FA. Specifically, BMI was independently associated with the genu [β=-.21; B=-.0024; 95% CI, -.0048 to -.0000; p=.05] and cingulate fibers [β=-.39; B=-.0035; 95% CI,-.0056 to -.0015; p<.001], even after controlling for vascular/inflammatory risk factors and blood markers. In contrast, BMI was no longer significantly associated with the fornix and middle/posterior regions of the corpus callosum after controlling for these markers. Results partially support a vascular/inflammatory hypothesis, but also suggest a more complex relationship between BMI and white matter characterized by potentially different neuroanatomic vulnerability.
PMCID: PMC3797689  PMID: 24147070

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