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1.  Resilience and psychosocial outcomes in parents of children with cancer 
Pediatric blood & cancer  2013;61(3):552-557.
Background
The psychosocial function of parents of children with cancer can impact the well-being of the entire family. Resilience resources are likely related to psychosocial outcomes and may be amenable to intervention. We hypothesized that parents with lower resources would report worse outcomes.
Methods
In the “Understanding Resilience in Parents of Children with Cancer” study, comprehensive surveys were mailed to consecutive, English-speaking parents of children with cancer who were treated at Seattle Children’s Hospital and completed therapy between 01/01/2009 and 12/31/2010. Resilience resources were measured by the Connor-Davidson Resilience Scale; outcome measures included psychological distress, health-related behaviors, social and family function, and perceived communication with the medical team.
Results
96 parents (86% of contactable) completed the survey. Compared to population norms, enrolled parents had lower resilience resources, higher psychological distress, and more commonly reported binge drinking. Conversely, they reported higher social support and family adaptability (p<0.001–0.006). Lower resilience resources were associated with higher distress, lower social support, and lower family function (p<0.001–0.007). Parents in the lowest quartile of resilience resources had higher odds of frequent sleep difficulties (OR 5.19, 95% CI 1.74,15.45), lower health satisfaction (OR 5.71, 95% CI 2.05,15.92), and decreased ability to express worries to the medical team (OR 4.00, 95% CI 1.43,11.18).
Conclusions
Parents of children with cancer are at risk for poor psychosocial outcomes and those with low resilience resources may be at greater risk. Interventions directed at promoting resilience resources may provide a novel and complimentary approach towards improving outcomes for families facing pediatric cancer.
doi:10.1002/pbc.24854
PMCID: PMC4066960  PMID: 24249426
resilience; psychosocial outcomes; parents; pediatric cancer; whole patient care
2.  Higher iron in the red nucleus marks Parkinson’s dyskinesia 
Neurobiology of aging  2012;34(5):1497-1503.
Dopamine cell loss and increased iron in the substantia nigra (SN) characterize Parkinson’s disease (PD), with cerebellar involvement increasingly recognized, particularly in motor compensation and levodopa-induced-dyskinesia (LID) development. Because the red nucleus (RN) mediates cerebellar circuitry, we hypothesized that RN iron changes may reflect cerebellum-related compensation, and/or the intrinsic capacity for LID development. We acquired high resolution MRI images from 23 Controls and 38 PD subjects [12 with (PD+DYS) and 26 without (PD−DYS) LID history]. Iron content was estimated from bilateral RN and SN transverse relaxation rates (R2*). PD subjects overall displayed higher R2* values in both the SN and RN. RN R2* values correlated with off-drug Unified Parkinson’s Disease Rating Scale-motor scores, but not disease duration or drug dosage. RN R2* values were significantly higher in PD+DYS subjects compared to Controls and PD−DYS; Controls and PD−DYS did not differ. The association of higher RN iron content with PD-related dyskinesia suggests increased iron content is involved in, or reflects, greater cerebellar compensatory capacity and thus increased likelihood of LID development.
doi:10.1016/j.neurobiolaging.2012.10.025
PMCID: PMC3570638  PMID: 23177595
Parkinson’s disease (PD); red nucleus; transverse relaxation rate (R2*); magnetic resonance imaging (MRI)
3.  Analysis of Time-to-Event and Duration Outcomes in Neonatal Clinical Trials with Twin Births 
Contemporary clinical trials  2008;30(2):150-154.
When conducting neonatal trials in pre-term and/or low-birth-weight infants, twins may represent 10–20% of the study sample. Frailty models and proportional hazards regression with a robust sandwich variance estimate are common approaches for handling correlated time-to-event data or duration outcomes that are subject to censoring. However, the operating characteristics of these methods for mixes of correlated and independent time-to-event data are not well established. Simulation studies were conducted to compare frailty models and proportional hazards regression models with a robust sandwich variance estimate to standard proportional hazards regression models to estimate the treatment effect in two-armed clinical trials. While overall frailty models showed the best performance, caution must be exercised as the interpretation of the parameters differs from the marginal models. Data from the National Institute of Child Health & Human Development sponsored PROPHET trial are used for illustration.
doi:10.1016/j.cct.2008.11.001
PMCID: PMC3606884  PMID: 19027881
correlated data; frailty models; robust variance
4.  The Study of Pathogen Resistance and Antimicrobial Use in Dementia: Study Design and Methodology 
Advanced dementia is characterized by the onset of infections and antimicrobial use is extensive. The extent to which this antimicrobial use is appropriate and contributes to the emergence of antimicrobial resistant bacteria is not known. The object of this report is to present the methodology established in the Study of Pathogen Resistance and Exposure to Antimicrobials in Dementia (SPREAD), and describe how challenges specific to this research were met. SPREAD is an ongoing, federally-funded, 5-year prospective cohort study initiated in September 2009. Subjects include nursing home residents with advanced dementia and their proxies recruited from 31 Boston-area facilities. The recruitment and data collection protocols are described. Characteristics of participant facilities are presented and compared to those nationwide. To date, 295 resident/proxy dyads have been recruited. Baseline and selected follow-up data demonstrate successful recruitment of subjects and repeated collection of complex data documenting infections, decision-making for these infections, and antimicrobial bacteria resistance among the residents. SPREAD integrates methods in dementia, palliative care and infectious diseases research. Its successful implementation further establishes the feasibility of conducting rigorous, multi-site NH research in advanced dementia, and the described methodology serves as a detailed reference for subsequent publications emanating from the study.
doi:10.1016/j.archger.2012.08.001
PMCID: PMC3502703  PMID: 22925431
dementia; palliative care; infections; nursing home; methodology
5.  Imaging nigral pathology and clinical progression in Parkinson's disease 
Background
The pattern of dopamine cell loss in Parkinson's disease is known to be prominent in the ventrolateral and caudal substantia nigra, but less severe in the dorsal and rostral region. Both diffusion tensor imaging and R2* relaxometry of the substantia nigra have been reported as potential markers for Parkinson's disease, but their relative ability to mark disease progression and differences in pathophysiological bases remains unclear.
Methods
High resolution T2-weigthed, R2*, and diffusion tensor imaging were obtained from 28 controls and 40 Parkinson's disease subjects [15 early-stage (disease duration≤1 year), 14 mid-stage (duration 2-5 years), and 11 late-stage (duration>5 years)]. Fractional anisotropy and R2* values in both rostral and caudal substantia nigra were obtained for all subjects, and clinical measures (disease duration; levodopa-equivalent daily dosage; “off”-drug Unified Parkinson's Disease Rating Scale motor score) were obtained for Parkinson's subjects.
Results
There was no correlation between fractional anisotropy and clinical measures, whereas R2* was strongly associated with disease progression. Compared to controls, fractional anisotropy in caudal substantia nigra was significantly decreased in Parkinson's disease patients of all stages, whereas in rostral substantia nigra it was decreased significantly only in the late-stage group. R2* in both substantia nigra regions was significantly increased in the mid-stage and late-stage, but not early-stage, of Parkinson's disease subjects.
Conclusions
These findings suggest that fractional anisotropy changes may mark early pathological changes in caudal substantia nigra, whereas the changes in R2* may more closely track Parkinson's disease's clinical progression after symptom onset.
doi:10.1002/mds.25182
PMCID: PMC3510346  PMID: 23008179
Parkinson's disease (PD); substantia nigra; diffusion tensor imaging (DTI); transverse relaxation rate (R2*); magnetic resonance imaging (MRI)
6.  Scales for the Evaluation of End-of-Life Care in Advanced Dementia: Sensitivity to Change 
The paucity of valid and reliable instruments designed to measure end-of-life experiences limits advanced dementia and palliative care research. Two end-of-life in dementia (EOLD) scales that evaluate the experiences of severely cognitively impaired persons and their health care proxies (HCP) have been developed: 1) symptom management (SM) and 2) satisfaction with care (SWC). The study objective was to examine the sensitivity of the EOLD scales to detect significant differences in clinically relevant outcomes in nursing home residents with advanced dementia. The SM-EOLD scale was sensitive to detecting changes in comfort among residents with pneumonia, pain, dyspnea, and receiving burdensome interventions. The SWC-EOLD scale was sensitive to detecting changes in HCP satisfaction with the care of residents when addressing whether the health care provider spent > 15 minutes discussing the resident’s advanced care planning, whether the physician counseled about the resident’s live expectancy, whether resident resided in a special care unit and whether the physician counseled possible resident health problems. This study extends the psychometric properties of the EOLD scales by showing the sensitivity to clinically meaningful change in these scales to specific outcomes related to end-of-life care and quality of life among residents with end-stage advanced dementia and their HCPs.
doi:10.1097/WAD.0b013e318247c41b
PMCID: PMC3424399  PMID: 22273800
Dementia; Nursing homes; End-of-life; Health care proxy; Sensitivity to change; Responsiveness
7.  INSOMNIA WITH OBJECTIVE SHORT SLEEP DURATION AND INCIDENT HYPERTENSION: THE PENN STATE COHORT 
Hypertension  2012;60(4):929-935.
Insomnia with objective short sleep duration appears to be a biologically more severe phenotype of the disorder. No longitudinal study to date has examined the association of this type of insomnia with incident hypertension using polysomnography. From a random, general population sample of 1741 adults of the Penn State Cohort, 1395 were followed-up after 7.5 years and 786 did not have hypertension at baseline. Hypertension was determined by a self-report of receiving treatment for high blood pressure. Chronic insomnia was defined as a complaint of insomnia lasting ≥ 1 year, while poor sleep was defined as moderate-to-severe sleep difficulties. All subjects underwent 8-hour polysomnography. Sleep disordered breathing (SDB) was defined as an obstructive apnea/hypopnea index ≥ 5. We used the median polysomnographic percent of sleep time to define short sleep duration (i.e., < 6 hours). We controlled for gender, race, age, caffeine, cigarettes, alcohol consumption, depression, SDB, diabetes, obesity, and blood pressure in our analyses. Compared to normal sleepers who slept ≥ 6 hours, the highest risk for incident hypertension was in chronic insomniacs with short sleep duration (OR= 3.8, 95% CI=1.6–9.0). The risk for incident hypertension in poor sleepers with short sleep duration was significantly increased but became marginally significant after controlling for obesity (OR= 1.6, 95% CI=0.9–2.8). Chronic insomnia with short sleep duration is associated with an increased risk for incident hypertension in a degree comparable to SDB. Objective short sleep duration in insomnia may serve as a useful predictor of the biological severity of the disorder.
doi:10.1161/HYPERTENSIONAHA.112.193268
PMCID: PMC3679545  PMID: 22892811
Insomnia; Polysomnography; Hypertension; Incidence
8.  Parent Perception of Healthy Infant and Toddler Growth 
Clinical pediatrics  2009;49(4):343-349.
We hypothesized that parents of infants prefer growth at higher percentiles and are averse to growth at lower percentiles. Of 279 participating parents, only 10% desired their child’s weight to be in the lowest quartile. For children weighing in the lowest quartile, 57% of parents thought their child’s weight was “too low.” In contrast, 66% of parents whose child’s weight was in the top quartile preferred their child weigh that much. When viewing hypothetical infant growth trajectories, 47% ranked a growth chart demonstrating growth along the 10th percentile for weight as “least healthy” of 6 growth patterns, and 29% chose charts showing an infant at the 90th percentile for weight at age 1 as “healthiest.” In conclusion, parents are averse to growth at the bottom of the weight growth chart but are much less likely to feel negatively about growth at higher percentiles. This is troubling given the childhood obesity epidemic.
doi:10.1177/0009922809343717
PMCID: PMC3623679  PMID: 19745095
infant; growth; growth chart; obesity
9.  Risk Factors for Incident Chronic Insomnia: A General Population Prospective Study 
Sleep Medicine  2012;13(4):346-353.
Objective
The few population-based, prospective studies that have examined risk factors of incident insomnia were limited by small sample size, short follow-up, and lack of data on medical disorders or polysomnography. We prospectively examined the associations between demographics, behavioral factors, psychiatric and medical disorders, and polysomnography with incident chronic insomnia.
Methods
From a random, general population sample of 1741 individuals of the adult Penn State Sleep Cohort, 1395 were followed-up after 7.5 years. Only subjects without chronic insomnia at baseline (n=1246) were included in this study. Structured medical and psychiatric history, personality testing, and 8-hour polysomnography were obtained at baseline. Structured sleep history was obtained at baseline and follow-up.
Results
Incidence of chronic insomnia was 9.3%, with a higher incidence in women (12.9%) than in men (6.2%). Younger age (20–35 years), non-white ethnicity, and obesity increased the risk of chronic insomnia. Poor sleep and mental health were stronger predictors of incident chronic insomnia compared to physical health. Higher scores in MMPI-2, indicating maladaptive personality traits, and excessive use of coffee at baseline predicted incident chronic insomnia. Polysomnographic variables, such as short sleep duration or sleep apnea, did not predict incident chronic insomnia.
Conclusion
Mental health, poor sleep, and obesity, but not sleep apnea, are significant risk factors for incident chronic insomnia. Focusing on these more vulnerable groups and addressing the modifiable risk factors may help reduce the incident of chronic insomnia, a common and chronic sleep disorder associated with significant medical and psychiatric morbidity and mortality.
doi:10.1016/j.sleep.2011.10.033
PMCID: PMC3319648  PMID: 22425576
chronic insomnia; incidence; physical health; mental health; general population
10.  Do Cortisol Concentrations Predict Short-Term Outcomes in Extremely Low Birth Weight Infants? 
Pediatrics  2008;122(4):775-781.
OBJECTIVE
Relative adrenal insufficiency in extremely low birth weight infants may contribute to significant morbidity and death. Our objective was to evaluate the relationship between cortisol concentrations and short-term outcomes.
METHODS
Cortisol concentrations were obtained for 350 intubated, extremely low birth weight infants at postnatal age of 12 to 48 hours and at day 5 to 7, as part of a multicenter, randomized trial of hydrocortisone treatment for prophylaxis of relative adrenal insufficiency. Death and short-term morbidity were monitored prospectively. Cortisol levels at each time point were divided into quartiles. The incidence rates of outcomes were determined for each quartile and for infants with cortisol values of <10th percentile or >90th percentile.
RESULTS
Median cortisol values were 16.0 μg/dL at baseline and 13.1 μg/dL on day 5 to 7 in the placebo group. Outcomes did not differ in each quartile between treatment and placebo groups. Low cortisol values at baseline or day 5 to 7 were not associated with increased morbidity or mortality rates and were not predictive of open-label hydrocortisone use. In fact, vasopressor use was lower for infants with lower cortisol values at baseline. Severe intraventricular hemorrhage was more frequent in infants with cortisol levels in the upper quartile at baseline, and values of >90th percentile were significantly associated with higher rates of death, severe intraventricular hemorrhage, periventricular leukomalacia, gastrointestinal perforation, and severe retinopathy of prematurity.
CONCLUSIONS
Low cortisol concentrations were not predictive of adverse short-term outcomes, but high cortisol concentrations were associated with severe intraventricular hemorrhage, and extremely elevated values were associated with morbidity and death. Low cortisol concentrations alone at these 2 time points did not identify the infants at highest risk for adverse outcomes. In contrast, high cortisol values were associated with increased morbidity and mortality rates.
doi:10.1542/peds.2007-2252
PMCID: PMC3586215  PMID: 18829801
bronchopulmonary dysplasia; extremely preterm infants; hydrocortisone; outcomes of high-risk infants
11.  Women's Preconceptional Health and Use of Health Services: Implications for Preconception Care 
Health Services Research  2008;43(1 Pt 1):54-75.
Objective
To improve understanding of women's use of health care before pregnancy, by analyzing how the health status and health risks of pre- and interconceptional women are associated with health services use.
Data Source
Data are from a cross-sectional random-digit dial telephone survey of a representative sample of 2002 women ages 18–45 years from the Central Pennsylvania Women's Health Study (CePAWHS). A subsample of 1,325 respondents with current reproductive capacity, classified by reproductive life stage (preconceptional or interconceptional), was analyzed.
Study Design
Bivariate and multiple logistic regression analyses were conducted to determine how health needs (including indices of health status and health risks related to adverse pregnancy outcomes) are associated with five indicators of health services use (receipt of a regular physical exam, obstetrician–gynecologist [ob/gyn] visit, receipt of a set of recommended screening services, receipt of health counseling services on general health topics, and receipt of pregnancy-related counseling), controlling for predisposing and enabling variables.
Principal Findings
Only half of women at risk of pregnancy report receiving counseling about pregnancy planning in the past year. One-third of women surveyed did not receive routine physical examinations and screening services, and over half received little or no health counseling. Multivariate analyses showed that all the measures of health needs except for negative health behavior were related to some type of health services use. Psychosocial stress was associated with having a recent ob/gyn visit, with receiving general health counseling, and with receiving pregnancy planning counseling. Cardiovascular risk was positively associated with receiving general health counseling and a regular physical exam, but negatively associated with seeing an ob/gyn. Positive health behaviors were associated with receiving screening services and with receiving general health counseling. Preconceptional reproductive life stage was positively associated with receiving a regular physical exam and negatively associated with having an ob/gyn visit.
Conclusions
Pre- and interconceptional women with specific health care needs may not receive appropriate health care before pregnancy. Improving pregnancy experiences and outcomes requires more comprehensive preconception health care and more preventive care before the first pregnancy.
doi:10.1111/j.1475-6773.2007.00741.x
PMCID: PMC2323151  PMID: 18211518
Women's health; pregnancy; preconception health; health care utilization; surveys
12.  Premature Cardiac Contractions and Risk of Incident Ischemic Stroke 
Background
The etiologies of ischemic stroke remain undetermined in 15% to 40% of patients. Apart from atrial fibrillation, other arrhythmias are less well-characterized as risk factors. Premature cardiac contractions are known to confer long-term cardiovascular risks, like myocardial infarction. Ischemic stroke as cardiovascular risk outcome remains a topic of interest. We examined the prospective relationships in the Atherosclerosis Risk in Communities (ARIC) study, to determine whether premature atrial (PAC) or ventricular (PVC) contractions are associated with increased risk for incident ischemic stroke.
Methods and Results
We analyzed 14 493 baseline stroke-free middle-aged individuals in the ARIC public-use data. The presence of PAC or PVC at baseline was assessed from 2-minute electrocardiogram. A physician-panel confirmed and classified all stroke cases. Average follow-up time was 13 years. Proportional hazards models assessed associations between premature contractions and incident stroke. PACs and PVCs were identified in 717 (4.9%) and 793 (5.5%) participants, respectively. In all, 509(3.5%) participants developed ischemic stroke. The hazard ratio (HR) (95% confidence interval [CI]) associated with PVC was 1.77 (1.30, 2.41), attenuated to 1.25 (0.91, 1.71) after adjusting for baseline stroke risk factors. The interaction between PVC and baseline hypertension was marginally significant (P=0.08). Among normotensives, having PVCs was associated with nearly 2-fold increase in the rate of incident ischemic stroke (HR 1.69; 95% CI 1.02, 2.78), adjusting for stroke risk factors. The adjusted risk of ischemic stroke associated with PACs was 1.30 (95% CI 0.92, 1.83).
Conclusions
Presence of PVCs may indicate an increased risk of ischemic stroke, especially in normotensives. This risk approximates risk of stroke from being black, male, or obese in normotensives from this cohort.
doi:10.1161/JAHA.112.002519
PMCID: PMC3541607  PMID: 23316293
brain ischemia; embolic stroke; premature atrial contraction; premature ventricular contraction; risk factors
13.  Combined R2* and diffusion tenser imaging changes in the substantia nigra in Parkinson disease 
Background
Recent magnetic resonance imaging (MRI) studies suggest increased transverse relaxation rate (R2*) and reduced diffusion tensor imaging (DTI) fractional anisotropy (FA) values in the SN in PD. The R2* and FA changes may reflect different aspects of PD-related pathological processes (i.e., tissue iron deposition and microstructure disorganization). This study investigated the combined changes of R2* and FA in the SN in PD.
Methods
High resolution MRI (T2-weighted, T2*, and DTI) were obtained from 16 PD and 16 Controls. Bilateral SNs were delineated manually on T2-weighted images and co-registered to R2* and FA maps. The mean R2* and FA values in each SN then were calculated and compared between PD and Controls. Logistic regression, followed by ROC curve analysis, was employed to investigate the sensitivity and specificity of the combined measures for differentiating PD subjects from Controls.
Results
Compared to Controls, PD subjects demonstrated increased R2* (p<0.0001) and reduced FA (p=0.0365) in the SN. There was no significant correlation between R2* and FA values. Logistic regression analyses indicated that the combined use of R2* and FA values provides excellent discrimination between PD and Controls (c-statistic=0.996) compared to R2* (c-statistic=0.930) or FA (c-statistic=0.742) alone.
Conclusions
This study shows that the combined use of R2* and FA measures in the SN of PD enhances the sensitivity and specificity in differentiating PD from Controls. Further studies are warranted to evaluate the pathophysiological correlations of these MRI measurements, and their effectiveness in assisting in diagnosing PD and following its progression.
doi:10.1002/mds.23643
PMCID: PMC3154471  PMID: 21618607
Parkinson’s disease (PD); substantia nigra; diffusion tensor imaging (DTI); transverse relaxation rate (R2*); magnetic resonance imaging (MRI)
14.  Systemic inflammation and circadian rhythm of cardiac autonomic modulation 
Systemic inflammation (SI) is associated with impairment of cardiac autonomic modulation (CAM), which is associated with cardiac disease. However, there is limited data about SI on CAM circadian pattern, which this study is aimed to investigate in a middle-aged sample. C-reactive protein (CRP) was used as a SI marker. We performed HRV analysis on each 5-minute segment RRs from of a 24-hour 12-lead ECG to obtain time and frequency domain HRV indices as measures of CAM. The circadian pattern of CAM was analyzed by a two-stage modeling. Stage one, for each individual we fit a cosine periodic model based on the 288 segments of 5-minute HRV data to produce three individual-level cosine parameters that quantity the circadian pattern: mean (M), amplitude (Â), and acrophase time (θ), measure the overall average, the amplitude of the oscillation, and the timing of the highest oscillation, respectively. Stage two, we used random-effects-meta-analysis to summarize the effects of CRP on the three circadian parameters obtained in stage one. CRP was adversely associated with lower M of log-HF, log-LF, SDNN, and RMSSD [β (SE): −0.22 (0.07) ms2, −0.20 (0.06) ms2, −3.62 (0.99) ms, and −2.32 (0.73) ms, respectively, with all p-values<0.01]. More importantly, CRP was also adversely associated with lower  of SDNN and RMSSD [β (SE): −0.84 (0.44) ms and −0.86 (0.38) ms, respectively, both p-values<0.05]. SI is adversely associated with circadian pattern of CAM, suggesting that the cardiac risk associated with SI may be partially mediated via inflammation-related changes in CAM.
doi:10.1016/j.autneu.2011.03.002
PMCID: PMC3111893  PMID: 21444250
C-reactive Protein; Inflammatory Marker; Heart Rate Variability; Periodic Regression; Random-effects Model; Meta-analysis; Community Population
15.  Grief among Family Members of Nursing Home Residents with Advanced Dementia 
Objectives
To describe pre-loss and post-loss grief symptoms among family members of nursing home (NH) residents with advanced dementia, and to identify predictors of greater post-loss grief symptoms.
Design
Prospective cohort study.
Setting
22 NHs in the greater Boston area.
Participants
123 family members of NH residents who died with advanced dementia.
Measurements
Pre-loss grief was measured at baseline, and post-loss grief was measured 2 and 7 months post-loss using the Prolonged Grief Disorder scale. Independent variables included resident and family member sociodemographic characteristics, resident comfort, acute illness, acute care prior to death, family member depression, and family member understanding of dementia and of resident’s prognosis.
Results
Levels of pre-loss and post-loss grief were relatively stable from baseline to 7 months post-loss. Feelings of separation and yearning were the most prominent grief symptoms. After multivariable adjustment, greater pre-loss grief and the family member having lived with the resident prior to NH admission were the only factors independently associated with greater post-loss grief 7 months after resident death.
Conclusions
The pattern of grieving for some family members of NH residents with advanced dementia is prolonged and begins before resident death. Identification of family members at risk for post-loss grief during the pre-loss period may help guide interventions aimed at lessening post-loss grief.
doi:10.1097/JGP.0b013e31820dcbe0
PMCID: PMC3101368  PMID: 21606897
dementia; grief; nursing homes
16.  Serum Cholesterol and Nigrostriatal R2* Values in Parkinson's Disease 
PLoS ONE  2012;7(4):e35397.
Background
The occurrence of Parkinson's disease (PD) is known to be associated both with increased nigrostriatal iron content and with low serum cholesterol and PD, but there has been no study to determine a potential relationship between these two factors.
Methods
High-resolution MRI (T1-, T2, and multiple echo T2*-weighted imaging) and fasting lipid levels were obtained from 40 patients with PD and 29 healthy controls. Iron content was estimated from mean R2* values (R2* = 1/T2*) calculated for each nigrostriatal structure including substantia nigra, caudate, putamen, and globus pallidus. This was correlated with serum cholesterol levels after controlling for age, gender, and statin use.
Results
In patients with PD, higher serum cholesterol levels were associated with lower iron content in the substantia nigra (R = −0.43, p = 0.011 for total-cholesterol, R = −0.31, p = 0.080 for low-density lipoprotein) and globus pallidus (R = −0.38, p = 0.028 for total-cholesterol, R = −0.27, p = 0.127 for low-density lipoprotein), but only a trend toward significant association of higher total-cholesterol with lower iron content in the striatum (R = −0.34, p = 0.052 for caudate; R = −0.32, p = 0.061 for putamen). After adjusting for clinical measures, the cholesterol-iron relationships held or became even stronger in the substantia nigra and globus pallidus, but weaker in the caudate and putamen. There was no significant association between serum cholesterol levels and nigrostriatal iron content for controls.
Conclusions
The data show that higher serum total-cholesterol concentration is associated with lower iron content in substantia nigra and globus pallidus in Parkinson's disease patients. Further studies should investigate whether this is mechanistic or epiphenomenological relationship.
doi:10.1371/journal.pone.0035397
PMCID: PMC3328461  PMID: 22530017
17.  Use of the Ages and Stages Questionnaire and Bayley Scales of Infant Development-II in Neurodevelopmental Follow-up of Extremely Low Birth Weight Infants 
Objectives
For infants born extremely low birth weight (ELBW), we examined the 1) correlation between results on the Ages and Stages Questionnaire (ASQ), and the Bayley Scales of Infant Development II (BSID-II) at 18-22 months corrected age; 2) degree to which earlier ASQ assessments predict later BSID-II results; 3) impact of ASQ use on follow-up study return rates.
Study Design
ASQ data were collected at 4, 8, 12, and 18-22 months corrected age. The BSID-II was completed at 18-22 months corrected age. ASQ and BSID-II 18 – 22 month sensitivity and specificity were examined. Ability of earlier ASQs to predict later BSID-II scores was examined through linear regression analyses.
Results
ASQ sensitivity and specificity at 18-22 months were 73% and 65%, respectively. Moderate correlation existed between earlier ASQ and later BSID-II results.
Conclusions
For ELBW infant assessment, the ASQ cannot substitute for the BSID-II, but appears to improve tracking success.
doi:10.1038/jp.2011.1
PMCID: PMC3139816  PMID: 21311498
Bayley Scales of Infant Development; Ages and Stages Questionnaire; neurodevelopment; developmental assessment; developmental screening; NICU
18.  Maturational and Aging Effects on Human Brain Apparent Transverse Relaxation 
PLoS ONE  2012;7(2):e31907.
The goal of this study was to address the need for comprehensive reference data regarding maturational and aging effects on regional transverse relaxation rates (R2) of the brain in normal humans. Regional R2s were measured in twenty-five brain structures from a sample of seventy-seven normal volunteers 9 to 85 years of age. The relationships between regional R2 and age were determined using generalized additive models, without the constraint of a specified a priori model. Data analysis demonstrated that the brain tissue R2-age correlations followed various time courses with both linear and non-linear characteristics depending on the particular brain structure. Most anatomical structures studied exhibited non-linear characteristics, including the amygdala, hippocampus, thalamus, globus pallidus, putamen, caudate nucleus, red nucleus, substantia nigra, orbitofrontal white matter and temporal white matter. Linear trends were detected in occipital white matter and in the genu of corpus callosum. These results indicate the complexity of age-related R2 changes in the brain while providing normative reference data that can be utilized in clinical examinations and studies utilizing quantitative transverse relaxation.
doi:10.1371/journal.pone.0031907
PMCID: PMC3283700  PMID: 22363767
19.  Hospice Utilization and Outcomes Among Nursing Home Residents with Advanced Dementia 
Objectives
To identify characteristics of nursing home (NH) residents with advanced dementia and their health care proxies (HCPs) associated with hospice referral; and examine the association between hospice use and 1) the treatment of pain and dyspnea, and 2) unmet needs during the last 7 days of life.
Design
Prospective cohort study.
Setting
Twenty-two Boston-area NHs.
Participants
323 NH residents with advanced dementia and their HCPs.
Measurements
Data were collected at baseline and quarterly up to 18 months. Hospice referral, the frequency pain and dyspnea were experienced, and treatment of these symptoms was ascertained. HCPs reported unmet needs during the last 7 days of the residents' lives for the following domains: communication, information, emotional support, and help with personal care.
Results
Twenty-two percent of residents were referred to hospice. After multivariable adjustment, factors associated with hospice referral included: non-White race, eating problems, HCP's perception the resident's prognosis was < 6 months, and better HCP mental health. Residents on hospice were more likely to receive scheduled opioids for pain (adjusted odds ratio (AOR), 3.16; 95% confidence interval (CI95%), 1.57-6.36), and oxygen, morphine, scopolamine or hyoscyamine for dyspnea (AOR, 3.28; CI95%, 1.37-7.86). HCPs of residents on hospice reported fewer unmet needs in all domains during the last 7 days of the residents' life.
Conclusion
A minority of NH residents with advanced dementia received hospice care. Hospice recipients were more likely to received scheduled opioids for pain and symptomatic treatment for dyspnea, and had fewer unmet needs at the end of life.
doi:10.1111/j.1532-5415.2010.03185.x
PMCID: PMC3057929  PMID: 21143437
Hospice; palliative care; Alzheimer's disease; dementia; nursing homes
20.  Prediction of 6-Month Survival of Nursing Home Residents With Advanced Dementia Using ADEPT vs Hospice Eligibility Guidelines 
Context
Estimating life expectancy is challenging in advanced dementia, potentially limiting the use of hospice care in these patients.
Objective
To prospectively validate and compare the performance of the Advanced Dementia Prognostic Tool (ADEPT) and hospice eligibility guidelines to estimate 6-month survival in nursing home residents with advanced dementia.
Design, Setting, and Participants
A prospective cohort study conducted in 21 nursing homes in Boston, Massachusetts, of 606 residents with advanced dementia who were recruited between November 1, 2007, and July 30, 2009. Data were ascertained at baseline to determine the residents’ ADEPT score (range, 1.0-32.5; higher scores indicate worse prognosis) and whether they met Medicare hospice eligibility guidelines. Survival was followed up to 6 months.
Main Outcome Measures
Assessment and comparison of the performance of the ADEPT score and hospice guidelines to predict 6-month survival using sensitivity, specificity, and the area under the receiver operating characteristic (AUROC) curve.
Results
At baseline, the residents’ mean (SD) ADEPT score was 10.1 (3.1) points and 65 residents (10.7%) met hospice eligibility guidelines. Over 6 months, 111 residents (18.3%) died. The AUROC for the ADEPT score’s prediction of 6-month mortality as a continuous variable was 0.67 (95% confidence interval [CI], 0.62-0.72). The AUROC for Medicare hospice eligibility guidelines was 0.55 (95% CI, 0.51-0.59), the specificity was 0.89 (95% CI, 0.86-0.92), and the sensitivity was 0.20 (95% CI, 0.13-0.28). Using a cutoff of 13.5 on the ADEPT score, which also had specificity of 0.89, the AUROC was 0.58 (95% CI, 0.54-0.63) and the sensitivity was 0.27 (95% CI, 0.19-0.36).
Conclusions
When prospectively validated at the bedside and used as a continuous measure, the ability of the ADEPT score to identify nursing home residents with advanced dementia at high risk of death within 6 months was modest, albeit better than hospice eligibility guidelines. Care provided to these residents should be guided by their goals of care rather than estimated life expectancy.
doi:10.1001/jama.2010.1572
PMCID: PMC3017367  PMID: 21045099
21.  The Advanced Dementia Prognostic Tool (ADEPT): A Risk Score to Estimate Survival in Nursing Home Residents with Advanced Dementia 
Context
Estimating life expectancy is challenging in advanced dementia.
Objectives
To create a risk score to estimate survival in nursing home (NH) residents with advanced dementia.
Methods
This was a retrospective cohort study performed in the setting of all licensed US NHs. Residents with advanced dementia living in US NHs in 2002 were identified using Minimum Data Set (MDS) assessments. Mortality data from Medicare files were used to determine 12-month survival. Independent variables were selected from the MDS. Cox proportional hazards regression was used to model survival. The accuracy of the final model was assessed using the area under the receiver operating characteristic curve (AUROC). To develop a risk score, points were assigned to variables in the final model based on parameter estimates. Residents meeting hospice eligibility guidelines for dementia, based on MDS data, were identified. The AUROC assessed the accuracy of hospice guidelines to predict six-month survival.
Results
Over 12 months, 40.6% of residents with advanced dementia (n=22,405) died. Twelve variables best predicted survival: length of stay, age, male, dyspnea, pressure ulcers, total functional dependence, bedfast, insufficient intake, bowel incontinence, body mass index, weight loss, and congestive heart failure. The AUROC for the final model was 0.68. The risk score ranged from 0–32 points (higher scores indicate worse survival). Only 15.9% of residents met hospice eligibility guidelines for which the AUROC predicting six-month survival was 0.53.
Conclusion
A mortality risk score derived from MDS data predicted six-month survival in advanced dementia with moderate accuracy. The predictive ability of hospice guidelines, simulated with MDS data, was poor.
doi:10.1016/j.jpainsymman.2010.02.014
PMCID: PMC2981683  PMID: 20621437
Survival; advanced dementia; mortality; nursing home; hospice; palliative care
22.  Randomized controlled trial of computerized tailored physical activity reports 
Background
Computerized, tailored interventions have the potential to be a cost-effective means to assist a wide variety of individuals with behavior change. To examine the effect of computerized tailored physical activity reports on primary care patients' physical activity at six months.
Design
Two-group randomized clinical trial with primary care physicians as the unit of randomization. Patients were placed in the intervention (n=187) or control group (n=207) based on their physician's assignment.
Setting/Participants
Primary care physicians (n=22) and their adult patients (n=394) from Philadelphia, PA. The study and analyses were conducted from 2004-2010.
Intervention
The intervention group completed physical activity surveys at baseline, one, three, and six months. Based on their responses, participants received four feedback reports at each time point. The reports aimed to motivate participants to increase physical activity, personalized to the participant's needs; they also included an activity prescription. The control group received identical procedures except they received general reports on preventive screening based on their responses to preventive screening questions.
Main outcome measure
Minutes of physical activity measured by the 7-Day Physical Activity Recall interview at six months.
Results
Participants were 69% female, 59% African American, and had diverse educational and income levels; the retention rate was 89.6%. After adjusting for baseline levels of activity and gender, the intervention group increased their total minutes of physical activity by a mean of 133 minutes, while the control group had a mean increase of 99 minutes (p=0.39).
Conclusions
Although we saw an increase in physical activity within both groups, computerized tailored physical activity reports did not significantly increase physical activity levels beyond control among ethnically and socioeconomically diverse adults in primary care.
doi:10.1016/j.amepre.2010.04.005
PMCID: PMC3140844  PMID: 20621262
primary care issues; physical activity; behavioral medicine; randomized clinical trial
23.  Survival and Comfort After Treatment of Pneumonia in Advanced Dementia 
Archives of internal medicine  2010;170(13):1102-1107.
Background
Pneumonia is common among patients with advanced dementia, especially toward the end of life. Whether antimicrobial treatment improves survival or comfort is not well understood. The objective of this study was to examine the effect of antimicrobial treatment for suspected pneumonia on survival and comfort in patients with advanced dementia.
Methods
From 2003 to 2009, data were prospectively collected from 323 nursing home residents with advanced dementia in 22 facilities in the area of Boston, Massachusetts. Each resident was followed up for as long as 18 months or until death. All suspected pneumonia episodes were ascertained, and antimicrobial treatment for each episode was categorized as none, oral only, intramuscular only, or intravenous (or hospitalization). Multivariable methods were used to adjust for differences among episodes in each treatment group. The main outcome measures were survival and comfort (scored according to the Symptom Management at End-of-Life in Dementia scale) after suspected pneumonia episodes.
Results
Residents experienced 225 suspected pneumonia episodes, which were treated with antimicrobial agents as follows: none, 8.9%; oral only, 55.1%, intramuscular, 15.6%, and intravenous (or hospitalization), 20.4%. After multivariable adjustment, all antimicrobial treatments improved survival after pneumonia compared with no treatment: oral (adjusted hazard ratio [AHR], 0.20; 95% confidence interval [CI], 0.10–0.37), intramuscular (AHR, 0.26; 95% CI, 0.12–0.57), and intravenous (or hospitalization) (AHR, 0.20; 95% CI, 0.09–0.42). After multivariable adjustment, residents receiving any form of antimicrobial treatment for pneumonia had lower scores on the Symptom Management at End-of-Life in Dementia scale (worse comfort) compared with untreated residents.
Conclusion
Antimicrobial treatment of suspected pneumonia episodes is associated with prolonged survival but not with improved comfort in nursing home residents with advanced dementia.
doi:10.1001/archinternmed.2010.181
PMCID: PMC2914628  PMID: 20625013
24.  Acute Effects of Fine Particulate Air Pollution on Cardiac Arrhythmia: The APACR Study 
Environmental Health Perspectives  2011;119(7):927-932.
Background: The mechanisms underlying the relationship between particulate matter (PM) air pollution and cardiac disease are not fully understood.
Objectives: We examined the effects and time course of exposure to fine PM [aerodynamic diameter ≤ 2.5 μm (PM2.5)] on cardiac arrhythmia in 105 middle-age community-dwelling healthy nonsmokers in central Pennsylvania.
Methods: The 24-hr beat-to-beat electrocardiography data were obtained using a high-resolution Holter system. After visually identifying and removing artifacts, we summarized the total number of premature ventricular contractions (PVCs) and premature atrial contractions (PACs) for each 30-min segment. A personal PM2.5 nephelometer was used to measure individual-level real-time PM2.5 exposures for 24 hr. We averaged these data to obtain 30-min average time–specific PM2.5 exposures. Distributed lag models under the framework of negative binomial regression and generalized estimating equations were used to estimate the rate ratio between 10-μg/m3 increases in average PM2.5 over 30-min intervals and ectopy counts.
Results: The mean ± SD age of participants was 56 ± 8 years, with 40% male and 73% non-Hispanic white. The 30-min mean ± SD for PM2.5 exposure was 13 ± 22 μg/m3, and PAC and PVC counts were 0.92 ± 4.94 and 1.22 ± 7.18. Increases of 10 μg/m3 in average PM2.5 concentrations during the same 30 min or the previous 30 min were associated with 8% and 3% increases in average PVC counts, respectively. PM2.5 was not significantly associated with PAC count.
Conclusion: PM2.5 exposure within approximately 60 min was associated with increased PVC counts in healthy individuals.
doi:10.1289/ehp.1002640
PMCID: PMC3222979  PMID: 21398201
cardiac arrhythmia; cardiovascular disease; PAC; particulate matter; PVC
25.  Daily Medication Use in Nursing Home Residents with Advanced Dementia 
Objectives
Many medications commonly used to treat chronic conditions have unclear benefits for nursing home (NH) residents with advanced dementia. This study describes the pattern and factors associated with daily medication use in this population.
Design, Setting, Participants
Residents with advanced dementia (N=323) from 22 Boston-area NHs were followed prospectively for 18 months.
Measurements
Data from residents’ records were used to determine the number or daily medications, specific drugs prescribed, and use of drugs deemed ‘never appropriate’ in advanced dementia. Resident characteristics associated with the use of more daily medications and drugs deemed inappropriate were examined.
Results
Residents were prescribed a mean of 5.9 ± 3.0 daily medications, and 37.5% received at least one medication considered ‘never appropriate’ in advanced dementia. Acetylcholinesterase inhibitors (15.8%) and lipid-lowering agents (12.1%) were the most common inappropriate drugs. Twenty-eight percent of residents took antipsychotics daily. Modest reductions of most daily medications only occurred during the last week of life. Factors independently associated with taking more daily medications included older age, male, non-white, dementia not due Alzheimer’s, better cognition, cardiovascular disease, acute illness, and hospice referral. Factors independently associated with greater likelihood of taking inappropriate medications included male, shorter NH stay, better functional status, and diabetes, while a do-not-hospitalize order was associated with a lower likelihood.
Conclusion
Questionably beneficial medications are common in advanced dementia, even as death approaches. Several characteristics can help identify residents at risk for greater medication burden. Medication use in advanced dementia should be tailored to the goals of care.
doi:10.1111/j.1532-5415.2010.02819.x
PMCID: PMC2910133  PMID: 20406320
end-of-life care; dementia; inappropriate medication use; nursing homes; polypharmacy

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