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1.  Clinical features and outcomes in patients with secondary Ewing sarcoma 
Pediatric blood & cancer  2012;60(4):611-615.
Background
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.
Procedure
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.
Results
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).
Conclusions
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.
doi:10.1002/pbc.24251
PMCID: PMC3488141  PMID: 22847990
2.  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.
Conclusions
Findings from this study suggest that, regardless of pain status, anxiety and depression are common problems in women prior to breast cancer surgery.
doi:10.1016/j.ejon.2012.06.001
PMCID: PMC3524405  PMID: 22892272
breast pain; breast cancer surgery; anxiety; depression; quality of life; psychological distress
3.  Likelihood-based analysis of longitudinal data from outcome-related sampling designs 
Biometrics  2013;70(1):44-52.
Summary
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.
doi:10.1111/biom.12108
PMCID: PMC3954410  PMID: 24571396
Conditional likelihood; Retrospective sampling; Subject-specific models
4.  Characteristics and Outcomes of Patients with Ewing Sarcoma Over 40 Years of Age at Diagnosis 
Cancer epidemiology  2012;37(1):29-33.
Background
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.
Methods
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.
Results
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.
Conclusion
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.
doi:10.1016/j.canep.2012.08.006
PMCID: PMC3543501  PMID: 22959474
Ewing sarcoma; pediatric cancers; adult; age; SEER
5.  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.
doi:10.1371/journal.pone.0086283
PMCID: PMC3897676  PMID: 24466003
6.  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) 
Background/Objectives
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.
Design
Longitudinal
Setting
Sacramento Area Study of Latinos (SALSA)
Participants
1,435 Mexican-Americans ages 60–101 with mean follow-up 6.8 years
Measurements
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.
Results
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).
Conclusions
Cystatin C may be a useful alternative in addition to creatinine to detect high risk CKD in elderly Mexican Americans.
doi:10.1111/jgs.12040
PMCID: PMC3545054  PMID: 23252993
chronic kidney disease; Mexican-Americans; elderly; creatinine; cystatin C; cardiovascular disease
7.  IDENTIFICATION OF PATIENT SUBGROUPS AND RISK FACTORS FOR PERSISTENT BREAST PAIN FOLLOWING BREAST CANCER SURGERY 
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.
doi:10.1016/j.jpain.2012.09.013
PMCID: PMC3511823  PMID: 23182226
breast pain; persistent postsurgical pain; risk factors; breast cancer surgery; growth mixture modeling; latent class analysis
8.  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.
doi:10.1371/journal.pone.0077741
PMCID: PMC3797689  PMID: 24147070
9.  Clinical Features and Outcomes in Patients with Ewing Sarcoma and Regional Lymph Node Involvement 
Pediatric blood & cancer  2011;59(4):617-620.
Background
A minority of patients with Ewing sarcoma present with regional lymph node involvement. We investigated if patient characteristics and outcomes differ between patients with Ewing sarcoma with and without regional node involvement.
Procedure
Patients < 40 years of age with Ewing sarcoma or peripheral primitive neuroectodermal tumor (PNET) reported to the SEER database from 1973 to 2008 were evaluated based on the presence (n=91) or absence (n=1361) of regional node involvement. Patient characteristics were analyzed using Fisher exact tests. Overall survival was estimated by Kaplan-Meier methods and evaluated using log-rank tests and Cox models.
Results
Patients with regional node involvement were more likely to have extraskeletal primary tumors (65.9% vs. 31.2%; p < 0.001) and axial tumors (71.1% vs. 59.6%; p = 0.03) compared to patients without regional node involvement. The incidence of regional node involvement was 12.4% for patients with extraskeletal primary tumors compared to 3.2% for patients with skeletal tumors. Five-year overall survival from diagnosis was inferior for patients with regional node involvement compared to those without regional node involvement (45.9% vs. 60.3%; p < 0.001). On multivariate analysis, regional node involvement was predictive of inferior overall survival independent of age, metastatic status, tumor site, and soft tissue origin (hazard ratio 1.59; 95% CI 1.16–2.19).
Conclusions
Patients with extraskeletal Ewing sarcoma should undergo evaluation for regional node involvement. If validated, our findings indicate that regional node involvement may be an independent adverse prognostic factor in Ewing sarcoma, and potentially useful in risk-stratifying patients with otherwise localized disease.
doi:10.1002/pbc.24053
PMCID: PMC3310932  PMID: 22184129
10.  Predictors of Acute Chemotherapy-Associated Toxicity in Patients with Ewing Sarcoma 
Pediatric blood & cancer  2011;59(4):611-616.
Background
Ewing sarcoma (ES) is a malignant tumor of bone and soft tissue of children and young adults. Patients with ES are treated with intensive chemotherapy regimens. We describe predictors of acute chemotherapy-associated toxicity in this population.
Procedure
In this retrospective cohort study, records of ES patients treated at two academic medical centers between 1980 and 2010 were reviewed. Grade 3 and 4 non-hematologic chemotherapy-associated toxicities during frontline therapy were recorded for each patient, along with potential clinical and demographic predictors of toxicity. Bivariate analyses were performed using the Fisher exact test. Multivariate analysis was performed using logistic regression.
Results
The cohort included 142 patients with ES and toxicity data. In bivariate analyses, age <12 years at diagnosis, Latino ethnicity, low family income, and treatment on a clinical trial were associated with higher incidence of toxicity (p <0.01). Tumor size, site, stage, mode of local control, body mass index, overall chemotherapy exposure and dose-intensity were not associated with toxicity. In multivariate analysis, low income (odds ratio (OR) 4.97, 95% CI 1.9–13.1), clinical trial enrollment (OR 3.67, 95% CI 1.2–10.9), pelvic tumor site (OR 3.88, 95% CI 1.17–12.88), and age <12 years (OR 2.8, 95% CI 1.0–7.5) were independent predictors of toxicity.
Conclusion
ES patients who are younger, of Latino ethnicity, have pelvic tumors or low income have higher rates of toxicity that may require increased supportive care. Treatment on a clinical trial was also associated with higher rates of toxicity, though this finding may reflect better reporting in these patients.
doi:10.1002/pbc.24031
PMCID: PMC3310949  PMID: 22180320
Ewing sarcoma; toxicity; income; ethnicity; age
11.  Children with Autism Show Reduced Somatosensory Response: An MEG Study 
Lay Abstract
Autism spectrum disorders are reported to affect nearly one out of every one hundred children, with over 90% of these children showing behavioral disturbances related to the processing of basic sensory information. Behavioral sensitivity to light touch, such as profound discomfort with clothing tags and physical contact, is a ubiquitous finding in children on the autism spectrum. In this study, we investigate the strength and timing of brain activity in response to simple, light taps to the fingertip. Our results suggest that children with autism show a diminished early response in the primary somatosensory cortex (S1). This finding is most evident in the left hemisphere. In exploratory analysis, we also show that tactile sensory behavior, as measured by the Sensory Profile, may be a better predictor of the intensity and timing of brain activity related to touch than a clinical autism diagnosis. We report that children with atypical tactile behavior have significantly lower amplitude somatosensory cortical responses in both hemispheres. Thus sensory behavioral phenotype appears to be a more powerful strategy for investigating neural activity in this cohort. This study provides evidence for atypical brain activity during sensory processing in autistic children and suggests that our sensory behavior based methodology may be an important approach to investigating brain activity in people with autism and neurodevelopmental disorders.
Scientific Abstract
The neural underpinnings of sensory processing differences in autism remain poorly understood. This prospective magnetoencephalography (MEG) study investigates whether children with autism show atypical cortical activity in the primary somatosensory cortex (S1) in comparison to matched controls. Tactile stimuli were clearly detectable, painless taps applied to the distal phalanx of the second (D2) and third (D3) fingers of the right and left hands. Three tactile paradigms were administered: an oddball paradigm (standard taps to D3 at an inter-stimulus interval (ISI) of 0.33 and deviant taps to D2 with ISI ranging from 1.32–1.64s); a slow-rate paradigm (D2) with an ISI matching the deviant taps in the oddball paradigm; and a fast-rate paradigm (D2) with an ISI matching the standard taps in the oddball. Study subjects were boys (age 7–11 years) with and without autism disorder. Sensory behavior was quantified using the Sensory Profile questionnaire. Boys with autism exhibited smaller amplitude left hemisphere S1 response to slow and deviant stimuli during the right hand paradigms. In post-hoc analysis, tactile behavior directly correlated with the amplitude of cortical response. Consequently, the children were re-categorized by degree of parent-report tactile sensitivity. This regrouping created a more robust distinction between the groups with amplitude diminution in the left and right hemispheres and latency prolongation in the right hemisphere in the deviant and slow-rate paradigms for the affected children. This study suggests that children with autism have early differences in somatosensory processing, which likely influence later stages of cortical activity from integration to motor response.
doi:10.1002/aur.1247
PMCID: PMC3474892  PMID: 22933354
Cognitive Neuroscience; Event Related Potential; School age; Low-level perception; Magnetoencephalography
12.  Memantine in frontotemporal lobar degeneration: A multicenter, randomised, double-blind, placebo-controlled trial 
Lancet neurology  2013;12(2):149-156.
Background
Memantine has been used off-label to treat frontotemporal lobar degeneration (FTD). A previous 26 week open label study suggested a transient, modest benefit on neuropsychiatric symptoms as measured by the Neuropsychiatric Inventory (NPI).
Methods
We performed a randomized, parallel group, double blind, placebo controlled trial of 20 mg memantine taken orally daily for 26 weeks in FTD. Participants met Neary criteria for behavioral variant (bvFTD) or semantic dementia (SD) and had characteristic brain atrophy. Use of cholinesterase inhibitors was prohibited. The objective of the study was to determine whether memantine is an effective treatment for FTD. Individuals were randomized to memantine or matched placebo tablets in blocks of two and four. Primary endpoints were the change in total NPI score and Clinical Global Impression of Change (CGIC) scores after 26 weeks. Secondary outcomes included a neuropsychological battery, and other cognitive, global and activity of daily living measures. Clinicaltrials.gov identifier: NCT00545974
Findings
100 subjects were screened, 81 were randomized, 5 (6%) discontinued and 76 completed all visits. Enrollment numbers were lower than planned due to many subjects’ preference to take memantine or cholinesterase inhibitors off-label rather than participate in a clinical trial. 39 memantine and 42 placebo subjects entered the primary intent to treat analysis. There was no effect of memantine treatment on either the NPI (mean difference [MD] 2.2, 95%CI: −3.9, 8.3, p = 0.47) or CGIC (MD 0, 95%CI: −0.4, 0.4, p = 0.90) after 26 weeks of treatment. Memantine was generally well tolerated, however there were more frequent cognitive adverse events in the memantine group.
Interpretation
There was no benefit of memantine treatment in bvFTD or SD. These data do not support memantine use in FTD.
Funding
Forest Research Institute
doi:10.1016/S1474-4422(12)70320-4
PMCID: PMC3756890  PMID: 23290598
13.  Anti-saccade performance predicts executive function and brain structure in normal elders 
Objective
To assess the neuropsychological and anatomical correlates of anti-saccade (AS) task performance in normal elders.
Background
The AS task correlates with neuropsychological measures of executive function and frontal lobe volume in neurological diseases, but has not been studied in a well-characterized normal elderly population. Because executive dysfunction can indicate an increased risk for cognitive decline in cognitively normal elders, we hypothesized that AS performance might be a sensitive test of age-related processes that impair cognition.
Method
The percentage of correct AS responses was evaluated in forty-eight normal elderly subjects and compared with neuropsychological test performance using linear regression analysis and gray matter volume measured on MRI scans using voxel-based morphometry.
Results
The percentage of correct AS responses was associated with measures of executive function, including modified trails, design fluency, Stroop inhibition, abstraction, and backward digit span, and correlated with gray matter volume in two brain regions involved in inhibitory control: the left inferior frontal junction and the right supplementary eye field. The association of AS correct responses with neuropsychological measures of executive function was strongest in individuals with fewer years of education.
Conclusions
The AS task is sensitive to executive dysfunction and frontal lobe structural alterations in normal elders.
doi:10.1097/WNN.0b013e318223f6c6
PMCID: PMC3775477  PMID: 21697711
anti-saccade; normal aging; executive function; frontal lobe; cognitive reserve
14.  The Association of Blood Pressure and Mortality Differs by Self-reported Walking Speed in Older Latinos 
Background.
In some older adults, higher blood pressure (BP) is associated with a lower risk of mortality. We hypothesized that higher BP would be associated with greater mortality in high-functioning elders and lower mortality in elders with lower functional status.
Methods.
Participants were 1,562 Latino adults aged 60–101 years in the Sacramento Area Latino Study on Aging. Functional status was measured by self-reported walking speed, and BP was measured by automatic sphygmomanometer. Death information was determined from vital statistics records.
Results.
There were 442 deaths from 1998 to 2010; 53% were cardiovascular. Mean BP levels (mmHg) varied across fast, medium, and slow walkers: 136, 139, and 140 mmHg (systolic), p = .02 and 75, 76, and 77 mmHg (diastolic), p = .08, respectively. The relationship between systolic BP and mortality varied by self-reported walking speed: The adjusted hazard ratio for mortality in slow walkers was 0.96 per 10 mmHg higher systolic BP (95% confidence interval: 0.89, 1.02) and 1.29 (95% confidence interval: 1.08, 1.55) in fast walkers (p value for interaction <.001). We found a similar pattern for diastolic BP, although the interaction did not reach statistical significance; the adjusted hazard ratio per 10 mmHg higher diastolic BP was 0.89 (95% confidence interval: 0.78, 1.02) in slow walkers and 1.20 (95% confidence interval: 0.82, 1.76) in fast walkers (p value for interaction = .06).
Conclusions.
In high-functioning older adults, elevated systolic BP is a risk factor for all-cause mortality. If confirmed in other studies, the assessment of functional status may help to identify persons who are most at-risk for adverse outcomes related to high BP.
doi:10.1093/gerona/glr245
PMCID: PMC3436088  PMID: 22389463
Blood pressure; Functional status; Latinos
15.  Placebo adherence and mortality in the Hormone and Estrogen/Progestin Replacement Study 
The American journal of medicine  2012;125(8):804-810.
Background
Analyses from double-blind randomized trials have reported lower mortality among participants who were more adherent to placebo compared with those who were less adherent. We explored this phenomenon by analyzing data from the placebo arm of the Heart and Estrogen/Progestin Replacement Study (HERS), a randomized, double-blind, placebo-controlled trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women.
Aims
Our primary aim was to measure and explain the association between adherence to placebo and total mortality among the placebo-allocated participants in the HERS trial. Secondary aims included assessment of the association between placebo adherence and cause-specific morbidity and mortality.
Methods
Participants with "higher placebo adherence" were defined as having taken at least 75% of their placebo study medication during each individual’s participation in the study, while those with “lower placebo adherence” took <75%. The primary outcome was in-study all-cause mortality.
Results
More adherent participants had significantly lower total mortality compared to less-adherent participants (HR = 0.52, 95% Confidence Interval: 0.29–0.93). Adjusting for available confounders did not change the magnitude or significance of the estimates. Analyses revealed that the association of higher adherence and mortality might be explained, in part, by time-dependent confounding.
Conclusions
Analyses of the HERS trial data support a strong association between adherence to placebo study medication and mortality. While probably not due to simple confounding by healthy lifestyle factors, the underlying mechanism for the association remains unclear. Further analyses of this association are necessary to explain this observation.
doi:10.1016/j.amjmed.2012.02.014
PMCID: PMC3423204  PMID: 22840666
Double-blind clinical trials; Placebo; Adherence
16.  Central Obesity, Leptin and Cognitive Decline: the Sacramento Area Latino Study on Aging 
Background/Aims
Central obesity is a risk factor for cognitive decline. Leptin is secreted by adipose tissue and has been associated with better cognitive function. Aging Mexican-Americans have higher levels of obesity than Non-Hispanic Whites, but no investigations examined the relationship between leptin and cognitive decline among them or the role of central obesity in this association.
Methods
We analyzed 1480 dementia-free older Mexican-Americans who were followed over ten years. Cognitive function was assessed every 12 to 15 months with the Modified Mini Mental State Exam (3MSE) and the Spanish and English Verbal Learning Test (SEVLT).
Results
For females with small waist circumference (≤35inches), an interquartile range (IQR) difference in leptin was associated with 35% less 3MSE errors and 22% less decline in SEVLT score over 10 years. For males with small waist circumference (≤40inches), an IQR difference in leptin was associated with 44% less 3MSE errors and 30% less decline in SEVLT score over 10 years. There was no association between leptin and cognitive decline among females or males with large waist circumference.
Conclusion
Leptin interacts with central obesity in shaping cognitive decline. Our findings provide valuable information about the effects of metabolic risk factors on cognitive function.
doi:10.1159/000339957
PMCID: PMC3483312  PMID: 22814127
Aging; cognition; obesity; leptin; longitudinal study; Mexican Americans
17.  Challenge of assessing symptoms in seriously ill intensive care unit patients: Can proxy reporters help?* 
Critical care medicine  2012;40(10):2760-2767.
Objectives
Determine levels of agreement among intensive care unit patients and their family members, nurses, and physicians (proxies) regarding patients’ symptoms and compare levels of mean intensity (i.e., the magnitude of a symptom sensation) and distress (i.e., the degree of emotionality that a symptom engenders) of symptoms among patients and proxy reporters.
Design
Prospective study of proxy reporters of symptoms in seriously ill patients.
Settings
Two intensive care units in a tertiary medical center in the Western United States.
Patients
Two hundred and forty-five intensive care unit patients, 243 family members, 103 nurses, and 92 physicians.
Interventions
None.
Measurements and Main Results
On the basis of the magnitude of intraclass correlation coefficients, where coefficients from .35 to .78 are considered to be appropriately robust, correlation coefficients between patients’ and family members’ ratings met this criterion (≥.35) for intensity in six of ten symptoms. No intensity ratings between patients and nurses had intraclass correlation coefficients >.32. Three symptoms had intensity correlation coefficients of ≥.36 between patients’ and physicians’ ratings. Correlation coefficients between patients and family members were >.40 for five symptom-distress ratings. No symptoms had distress correlation coefficients of ≥.28 between patients’ and nurses’ ratings. Two symptoms had symptom-distress correlation coefficients between patients’ and physicians’ ratings at >.39. Family members, nurses, and physicians reported higher symptom-intensity scores than patients did for 80%, 60%, and 60% of the symptoms, respectively. Family members, nurses, and physicians reported higher symptom-distress scores than patients did for 90%, 70%, and 80% of the symptoms, respectively.
Conclusions
Patient–family intraclass correlation coefficients were sufficiently close for us to consider using family members to help assess intensive care unit patients’ symptoms. Relatively low intraclass correlation coefficients between intensive care unit clinicians’ and patients’ symptom ratings indicate that some proxy raters overestimate whereas others underestimate patients’ symptoms. Proxy overestimation of patients’ symptom scores warrants further study because this may influence decisions about treating patients’ symptoms.
doi:10.1097/CCM.0b013e31825b94d8
PMCID: PMC3712644  PMID: 22890258
concordance; critical care; intensive care unit; proxy reporters; symptoms; symptom assessment
18.  Neuropsychological correlates of dominance, warmth, and extraversion in neurodegenerative disease 
Introduction
Changes in personality differ qualitatively and quantitatively between patients with different neurodegenerative diseases, likely due to divergent patterns of regional neurodegeneration. Regional damage to circuits underlying various cognitive and emotional functions have been associated with interpersonal traits like dominance, extraversion, and warmth in patients with neurodegenerative diseases, suggesting that personality may in part be mediated by these more basic neuropsychological functions. In this study, we hypothesized that different combinations of cognitive, neuropsychiatric, and emotional measures would predict different interpersonal traits in patients with neurodegenerative diseases.
Methods
A battery of cognitive, neuropsychiatric, and emotional measures was administered to 286 patients with various neurodegenerative diseases such as Alzheimer’s disease, behavioral variant frontotemporal dementia, semantic dementia, and progressive supranuclear palsy, and informants described patients’ dominance, extraversion, and warmth using the Interpersonal Adjective Scales (IAS) personality questionnaire. Regression modeling was performed to identify which neuropsychological factors uniquely predicted current personality, controlling for age, gender, and premorbid personality.
Results
Social dominance covaried with patients’ capacity for cognitive control and verbal fluency. Conversely, warmth did not rely on these executive or verbal skills, but covaried primarily with patients’ capacity for emotional responsiveness. Extraversion, representing a blend of dominance and warmth, demonstrated an intermediate degree of relationship to both executive/verbal and emotional functions.
Conclusions
These findings suggest that different personality traits are partly subserved by specific cognitive and emotional functions in neurodegenerative disease patients. While this study was performed in the context of brain damage, the results raise the question of whether individual differences in these neuropsychological abilities may also underlie variability in normal personality.
doi:10.1016/j.cortex.2011.03.001
PMCID: PMC3132224  PMID: 21470601
personality; neurodegenerative disease; cognition; emotion
19.  Adherence to placebo and mortality in the Beta Blocker Evaluation of Survival Trial (BEST) 
Contemporary Clinical Trials  2012;33(3):492-498.
Background
Randomized controlled trials have reported lower mortality among patients who adhere to placebo compared with those who do not. We explored this phenomenon by reanalyzing data from the placebo arm of the Beta Blocker Evaluation of Survival Trial (BEST), a randomized, double-blind, placebo-controlled trial of bucindolol and mortality.
Aims
Our primary aim was to measure and explain the association between adherence to placebo and total mortality among the placebo-allocated participants in the BEST trial. Secondary aims included assessment of the association between placebo adherence and cause-specific mortality.
Methods
Participants with "higher placebo adherence" were defined as having taken at least 75% of their placebo study medication over the entire course of each individual’s participation in the study, while those with “lower placebo adherence” took <75%. Primary outcome was in-study all-cause mortality. To account for confounding, we adjusted for all available modifiable, non-modifiable and psychosocial variables.
Results
Adherent participants had a significantly lower total mortality compared to less-adherent participants (HR = 0.61, 95% Confidence Interval: 0.46–0.82). Adjusting for available confounders did not change the magnitude or significance of the estimates. When considering cause-specific mortality, CVD and pump failure showed similar associations.
Conclusions
Analyses of the BEST trial data support a strong association between adherence to placebo study medication and total mortality. While probably not due to publication bias or simple confounding by healthy lifestyle factors, the underlying explanation for the association remains a mystery. Prospective examination of this association is necessary to better understand the underlying mechanism of this observation.
doi:10.1016/j.cct.2011.12.003
PMCID: PMC3312975  PMID: 22265975
Double-blind clinical trials; Placebo; Adherence
20.  Associations Between Pro- and Anti-Inflammatory Cytokine Genes and Breast Pain in Women Prior to Breast Cancer Surgery 
The Journal of Pain  2012;13(5):425-437.
Study purposes were to determine the occurrence rate for preoperative breast pain; describe the characteristics of this pain; evaluate for differences in demographic and clinical characteristics; and evaluate for variations in pro- and anti-inflammatory cytokine genes between women who did and did not report pain. Patients (n=398) were recruited prior to surgery and completed self-report questionnaires on a number of pain characteristics. Genotyping was done using a custom genotyping array. Women (28.2%) who reported breast pain were significantly younger (p < 0.001); more likely to be non-white (p= 0.032); reported significantly lower Karnofsky Performance Status scores (p = 0.008); were less likely to be post menopausal (p = 0.012), and had undergone significantly more biopsies (p=0.006). Carriers of the minor allele for a single nucleotide polymorphism (SNP) in interleukin (IL)1-receptor 1 (IL1R1) (rs2110726) were less likely to report breast pain prior to surgery (p = 0.007). Carriers of the minor allele for a SNP in IL13 (rs1295686) were more likely to report breast pain prior to surgery (p= 0.019). Findings suggest that breast pain occurs in over a quarter of women who are about to undergo breast cancer surgery. Based on phenotypic and genotypic characteristics found, inflammatory mechanisms contribute to preoperative breast pain.
doi:10.1016/j.jpain.2011.02.358
PMCID: PMC3348353  PMID: 22515947
breast pain; inflammation; cytokine genes; preoperative pain
21.  Lymphatic and Angiogenic Candidate Genes Predict the Development of Secondary Lymphedema following Breast Cancer Surgery 
PLoS ONE  2013;8(4):e60164.
The purposes of this study were to evaluate for differences in phenotypic and genotypic characteristics in women who did and did not develop lymphedema (LE) following breast cancer treatment. 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 four genes (i.e., lymphocyte cytosolic protein 2 (rs315721), neuropilin-2 (rs849530), protein tyrosine kinase (rs158689), vascular cell adhesion molecule 1 (rs3176861)) and three haplotypes (i.e., Forkhead box protein C2 (haplotype A03), neuropilin-2 (haplotype F03), vascular endothelial growth factor-C (haplotype B03)) involved in lymphangiogensis and angiogenesis. These genetic associations suggest a role for a number of lymphatic and angiogenic genes in the development of LE following breast cancer treatment.
doi:10.1371/journal.pone.0060164
PMCID: PMC3629060  PMID: 23613720
22.  The effect of misspecification of random effects distributions in clustered data settings with outcome-dependent sampling 
Genetic epidemiologists often gather outcome-dependent samples of family data to measure within-family associations of genetic factors with disease outcomes. Generalized linear mixed models provide effective methods to estimate within-family associations but typically require parametric specification of the random effects distribution. Although misspecification of the random effects distribution often leads to little bias in estimated regression coefficients in standard, prospective clustered data settings, some recent studies suggest that such misspecification will impact parameter estimates from outcome-dependent cluster sampling designs. Using analytic results, simulation studies and fits to example data, this study examines the effect of misspecification of random effects distributions on parameter estimates in clustered data settings with outcome-dependent sampling. We show that the effects are consistent with results from prospective cluster sampling settings. In particular, ascertainment corrected mixed model methods that assume normally distributed random intercepts and conditional likelihood approaches provide accurate estimates of within-family covariate effects even under a misspecified random effects distribution.
doi:10.1002/cjs.10117
PMCID: PMC3508766  PMID: 23204632
Ascertainment correction; conditional likelihood; generalized linear mixed models; misspecified mixing distributions
23.  IDENTIFICATION OF DISTINCT DEPRESSIVE SYMPTOM TRAJECTORIES IN WOMEN FOLLOWING SURGERY FOR BREAST CANCER 
Objective
Most longitudinal studies of depressive symptoms reported mean symptom scores that tend to obscure interindividual heterogeneity in the symptom experience. The identification of subgroups of patients with distinct trajectories of depressive symptoms may help identify high risk individuals who require an intervention. This study aimed to identify subgroups of breast cancer patients (n=398) with distinct trajectories of depressive symptoms in the first six months after surgery, as well as predictors of these trajectories.
Methods
Growth mixture modeling was used to identify the latent classes based on Center for Epidemiological Studies-Depression scale scores completed prior to and monthly for six months after surgery.
Results
Four latent classes of patients with distinct depressive symptom trajectories were identified: Resilient (38.9%), Subsyndromal (45.2%), Delayed (11.3%), and Peak (4.5%). Patients in the Subsyndromal class were significantly younger than patients in the Resilient class. Compared to the Resilient class, Subsyndromal, Delayed, and Peak classes had higher mean trait and state anxiety scores prior to surgery. Except for axillary lymph node dissection (ALND), disease- and treatment-related characteristics did not differ across the classes. A greater proportion of women in the Subsyndromal class had an ALND compared to those in the Resilient class.
Conclusions
Breast cancer patients experience different trajectories of depressive symptoms after surgery. Of note, over 60% of these women were classified into one of three distinct subgroups with clinically significant levels of depressive symptoms. Identification of phenotypic and genotypic predictors of symptom trajectories after cancer treatment warrants additional investigation.
doi:10.1037/a0024366
PMCID: PMC3217116  PMID: 21728421
breast cancer; depression; anxiety; growth mixture modeling; latent profiles; psychological distress
24.  Evaluation of Norepinephrine Transporter Expression and Metaiodobenzylguanidine Avidity in Neuroblastoma: A Report from the Children's Oncology Group 
Purpose. 123I-metaiodobenzylguanidine (MIBG) is used for the diagnostic evaluation of neuroblastoma. We evaluated the relationship between norepinephrine transporter (NET) expression and clinical MIBG uptake. Methods. Quantitative reverse transcription PCR (N = 82) and immunohistochemistry (IHC; N = 61) were performed for neuroblastoma NET mRNA and protein expression and correlated with MIBG avidity on diagnostic scans. The correlation of NET expression with clinical features was also performed. Results. Median NET mRNA expression level for the 19 MIBG avid patients was 12.9% (range 1.6–73.7%) versus 5.9% (range 0.6–110.0%) for the 8 nonavid patients (P = 0.31). Median percent NET protein expression was 50% (range 0–100%) in MIBG avid patients compared to 10% (range 0–80%) in nonavid patients (P = 0.027). MYCN amplified tumors had lower NET protein expression compared to nonamplified tumors (10% versus 50%; P = 0.0002). Conclusions. NET protein expression in neuroblastoma correlates with MIBG avidity. MYCN amplified tumors have lower NET protein expression.
doi:10.1155/2012/250834
PMCID: PMC3463166  PMID: 23050139
25.  Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia 
Brain  2011;134(9):2456-2477.
Based on the recent literature and collective experience, an international consortium developed revised guidelines for the diagnosis of behavioural variant frontotemporal dementia. The validation process retrospectively reviewed clinical records and compared the sensitivity of proposed and earlier criteria in a multi-site sample of patients with pathologically verified frontotemporal lobar degeneration. According to the revised criteria, ‘possible’ behavioural variant frontotemporal dementia requires three of six clinically discriminating features (disinhibition, apathy/inertia, loss of sympathy/empathy, perseverative/compulsive behaviours, hyperorality and dysexecutive neuropsychological profile). ‘Probable’ behavioural variant frontotemporal dementia adds functional disability and characteristic neuroimaging, while behavioural variant frontotemporal dementia ‘with definite frontotemporal lobar degeneration’ requires histopathological confirmation or a pathogenic mutation. Sixteen brain banks contributed cases meeting histopathological criteria for frontotemporal lobar degeneration and a clinical diagnosis of behavioural variant frontotemporal dementia, Alzheimer’s disease, dementia with Lewy bodies or vascular dementia at presentation. Cases with predominant primary progressive aphasia or extra-pyramidal syndromes were excluded. In these autopsy-confirmed cases, an experienced neurologist or psychiatrist ascertained clinical features necessary for making a diagnosis according to previous and proposed criteria at presentation. Of 137 cases where features were available for both proposed and previously established criteria, 118 (86%) met ‘possible’ criteria, and 104 (76%) met criteria for ‘probable’ behavioural variant frontotemporal dementia. In contrast, 72 cases (53%) met previously established criteria for the syndrome (P < 0.001 for comparison with ‘possible’ and ‘probable’ criteria). Patients who failed to meet revised criteria were significantly older and most had atypical presentations with marked memory impairment. In conclusion, the revised criteria for behavioural variant frontotemporal dementia improve diagnostic accuracy compared with previously established criteria in a sample with known frontotemporal lobar degeneration. Greater sensitivity of the proposed criteria may reflect the optimized diagnostic features, less restrictive exclusion features and a flexible structure that accommodates different initial clinical presentations. Future studies will be needed to establish the reliability and specificity of these revised diagnostic guidelines.
doi:10.1093/brain/awr179
PMCID: PMC3170532  PMID: 21810890
behavioural variant frontotemporal dementia; diagnostic criteria; frontotemporal lobar degeneration; FTD; pathology

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